bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2025–04–20
47 papers selected by
Viktor Korolchuk, Newcastle University
  1. The Role of WIPI2, ATG16L1 and ATG12-ATG5 in selective and nonselective autophagy.
  2. Autophagy: The convergence point of aging and cancer.
  3. POLR1D, a shared subunit of RNA polymerase I and III, modulates mTORC1 activity.
  4. Hepatic MC3R is a regulator of lipid droplet autophagy and liver steatosis.
  5. ATG9A controls all stages of autophagosome biogenesis.
  6. Usutu virus NS4A induces autophagy and is targeted by the selective autophagy receptor p62/SQSTM1 for degradation.
  7. FGF21 Activates Autophagy to Ameliorate Lipid Accumulation in NAFLD.
  8. Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging.
  9. A variant of the autophagic receptor NDP52 counteracts phospho-TAU accumulation and emerges as a protective factor for Alzheimer's disease.
  10. RabGAP1L modulates Rab7A and Rab10 to orchestrate cell-autonomous immunity.
  11. Hepatitis B surface antigen hijacks TANK-binding kinase 1 to suppress type I interferon and induce early autophagy.
  12. Research progress of autophagy in the pathogenesis of bronchial asthma.
  13. Autophagy and Its Association with Macrophages in Clonal Hematopoiesis Leading to Atherosclerosis.
  14. Sustained mTORC1 activation in activated T cells impairs vaccine responses in older individuals.
  15. Upregulating mTOR/S6 K Pathway by CASTOR1 Promotes Astrocyte Proliferation and Myelination in Gpam-/--induced mouse model of cerebral palsy.
  16. The role of Bcl‑2 in controlling the transition between autophagy and apoptosis (Review).
  17. The role of autophagy in cancer: from molecular mechanism to therapeutic window.
  18. Animal studies reveal downregulation of the Beclin-1 autophagy pathway as shared mechanism in Autism Spectrum Disorder: a systematic review and meta-analysis.
  19. Identification of new candidates regulating autophagy-dependent midgut degradation in Drosophila melanogaster.
  20. Crosstalk Between Autophagy and Oxidative Stress in Hematological Malignancies: Mechanisms, Implications, and Therapeutic Potential.
  21. The Interplay Between Autophagy and Apoptosis in the Mechanisms of Action of Stilbenes in Cancer Cells.
  22. Mitophagy in Brain Injuries: Mechanisms, Roles, and Therapeutic Potential.
  23. PAC-1 Synergizes with Sunitinib to Enhance Cell Death in Pancreatic Neuroendocrine Tumors.
  24. The Spectrum of Small Heat Shock Protein B8 (HSPB8)-Associated Neuromuscular Disorders.
  25. N6-Methyladenosine Modification in the Metabolic Dysfunction-Associated Steatotic Liver Disease.
  26. CYB5A promotes osteogenic differentiation of MC3T3-E1 cells through autophagy mediated by the AKT/mTOR/ULK1 signaling pathway.
  27. A ROS-Responsive nanoparticle for nuclear gene delivery and autophagy restoration in Parkinson's disease therapy.
  28. Lysosomal Dysfunction in Amyotrophic Lateral Sclerosis: A Familial Case Linked to the p.G376D TARDBP Mutation.
  29. Mitochondrial quality control in hematopoietic stem cells: mechanisms, implications, and therapeutic opportunities.
  30. Immunomodulatory roles of autophagic flux and IFIT in human ectocervical cells upon Trichomonas vaginalis infection.
  31. Role of Extracellular Vesicles in TSC Renal Cystogenesis.
  32. Autophagy, ER-phagy and ER dynamics during cell differentiation.
  33. Roles of Oxidative Stress and Autophagy in Alcohol-Mediated Brain Damage.
  34. Saturated Phosphatidic Acids Induce mTORC1-Driven Integrated Stress Response Contributing to Glucolipotoxicity in Hepatocytes.
  35. Induced proximity to PML protects TDP-43 from aggregation via SUMO-ubiquitin networks.
  36. A novel mechanism of FBXW7 in combating intervertebral disc degeneration: Mitigating ferroptosis in nucleus pulposus cells through the regulation of mitophagy.
  37. Autophagy induction enhances homologous recombination-associated CRISPR-Cas9 gene editing.
  38. KRASG12C/mTORC1 inhibition: a powerful duo in NSCLC therapeutics.
  39. Dual roles of CXCR4 (C-X-C motif chemokine receptor 4) in promoting entry of ebolavirus and targeting excessive glycoprotein for reticulophagic degradation to facilitate viral fitness.
  40. Autophagy-deficient budding yeast cells are sensitive to freeze-thaw stress.
  41. Bryostatin-1 improves function in arteries with suppressed endothelial cell autophagy.
  42. STAR/STARD1: a mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
  43. Inhibiting the Histone Demethylase Kdm4a Restrains Cardiac Fibrosis After Myocardial Infarction by Promoting Autophagy in Premature Senescent Fibroblasts.
  44. German longevity study reveals novel rare pro-longevity alleles clustering in mTOR signaling pathway.
  45. Sphingolipidoses: expanding the spectrum of α-synucleinopathies.
  46. Multi-omics analysis of two rat models reveals potential role of vesicle transport and autophagy in right ventricular remodeling.
  47. Protein-responsive gut hormone tachykinin directs food choice and impacts lifespan.
  1. J Mol Biol. 2025 Apr 10. pii: S0022-2836(25)00204-9. [Epub ahead of print] 169138
    The Role of WIPI2, ATG16L1 and ATG12-ATG5 in selective and nonselective autophagy.
    Daniele Campisi, N'Toia Hawkins, Kennedy Bonjour, Thomas Wollert.
      Autophagy is a conserved cellular recycling pathway that delivers damaged or superfluous cytoplasmic material to lysosomes for degradation. In response to cytotoxic stress or starvation, autophagy can also sequester bulk cytoplasm and deliver it to lysosomes to regenerate building blocks. In macroautophagy, a membrane cisterna termed phagophore that encloses autophagic cargo is generated. The formation of the phagophore depends on a conserved machinery of autophagy related proteins. The phosphatidylinositol(3)-phosphate binding protein WIPI2 facilitates the transition from phagophore initiation to phagophore expansion by recruiting the ATG12-ATG5-ATG16L1 complex to phagophores. This complex functions as an E3-ligase to conjugate ubiquitin-like ATG8 proteins to phagophore membranes, which promotes tethering of cargo to phagophore membranes, phagophore expansion, maturation and the fusion of autophagosomes with lysosomes. ATG16L1 also has important functions independently of ATG12-ATG5 in autophagy and beyond. In this review, we will summarize the functions of WIPI2 and ATG16L1 in selective and nonselective autophagy.
    DOI:  https://doi.org/10.1016/j.jmb.2025.169138
  2. Biochem Biophys Rep. 2025 Jun;42 101986
    Autophagy: The convergence point of aging and cancer.
    Anchala Pandey, Ankit Goswami, B Jithin, Sanjeev Shukla.
      Autophagy, a dynamic intracellular degradation system, is critical for cellular renovation and maintaining equilibrium. By eliminating damaged components and recycling essential molecules, autophagy safeguards cellular integrity and function. The versatility of the autophagy process across various biological functions enable cells to adapt and maintain homeostasis under unfavourable conditions. Disruptions in autophagy can shift a cell from a healthy state to a disease state or, conversely, support a return to health. This review delves into the multifaceted role of autophagy during aging and age-related diseases such as cancer, highlighting its significance as a unifying target with promising therapeutic implications. Cancer development is a dynamic process characterized by the acquisition of diverse survival capabilities for proliferating at different stages. This progression unfolds over time, with cancer cells exploiting autophagy to overcome encountered stress conditions during tumor development. Notably, there are several common pathways that utilize the autophagy process during aging and cancer development. This highlights the importance of autophagy as a crucial therapeutic target, holding the potential to not only impede the growth of tumor but also enhance the patient's longevity. This review aims to simplify the intricate relationship between cancer and aging, with a particular focus on the role of autophagy.
    DOI:  https://doi.org/10.1016/j.bbrep.2025.101986
  3. Biochim Biophys Acta Mol Cell Res. 2025 Apr 11. pii: S0167-4889(25)00062-X. [Epub ahead of print] 119957
    POLR1D, a shared subunit of RNA polymerase I and III, modulates mTORC1 activity.
    Neuton Gorjão, Lukasz S Borowski, Roman J Szczesny, Damian Graczyk.
      The mechanistic target of rapamycin complex 1 (mTORC1) is a crucial nutrient sensor and a major regulator of cell growth and proliferation. While mTORC1 activity is frequently upregulated in cancer, the mechanisms regulating mTORC1 are not fully understood. POLR1D, a shared subunit of RNA polymerases I and III, is often upregulated in colorectal cancer (CRC) and mutated in Treacher-Collins syndrome. POLR1D, together with its binding partner POLR1C, forms a dimer that is believed to initiate the assembly of the multisubunit RNA polymerases I and III. Our data reveal an unexpected link between POLR1D and mTORC1 signalling. We found that the overproduction of POLR1D in human cells stimulates mTORC1 activity. In contrast, the downregulation of POLR1D leads to the repression of the mTORC1 pathway. Additionally, we demonstrate that a pool of POLR1D localises to the cytoplasm and interacts with the mTORC1 regulator RAGA and RAPTOR. Furthermore, POLR1D enhances the interaction between RAPTOR and RAGA and sustains mTORC1 activity under starvation conditions. We have identified a novel role for the RNA polymerase I/III subunit POLR1D in regulating mTORC1 signalling. Our findings suggest the existence of a new node in the already complex mTORC1 signalling network, where POLR1D functions to convey the cell's internal status, namely polymerase assembly, to this kinase.
    Keywords:  POLR1D; RNA polymerase III; mTORC1
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119957
  4. Autophagy. 2025 Apr 17.
    Hepatic MC3R is a regulator of lipid droplet autophagy and liver steatosis.
    Tushar P Patel, Jack A Yanovski.
      Intrahepatic triglyceride breakdown and recycling occur through lipolysis and lipid droplet (LD) macroautophagy/autophagy to regulate systemic fat partitioning. We recently demonstrated that MC3R is important for hepatic autophagy and peripheral metabolism, beyond its established functions in the CNS, where it affects energy homeostasis, feeding regulation, and puberty. MC3R agonists activate hepatocyte autophagy through LC3-II activation, TFEB cytoplasmic-to-nuclear translocation, and subsequent downstream autophagy gene activation. Global mc3r knockout mice develop obesity with increased hepatic triglyceride accumulation and blunted hepatocellular autophagosome-lysosome docking, leading to defective lipid droplet clearance. Hepatic Mc3r reactivation in global knockouts improves hepatocellular autophagy, lipid metabolism, mitochondrial respiration, energy expenditure, body fat, and body weight. These results reveal an autonomous role for hepatic MC3R in regulating lipid droplet autophagy, liver steatosis, and systemic adiposity.
    Keywords:  Fatty liver disease; MC3R; TFEB; lipophagy; obesity
    DOI:  https://doi.org/10.1080/15548627.2025.2495224
  5. Autophagy. 2025 Apr 16.
    ATG9A controls all stages of autophagosome biogenesis.
    Ruheena Javed, Muriel Mari, Einar Trosdal, Thabata Lopes Alberto Duque, Masroor Paddar, Lee Allers, Prithvi Akepati, Michal H Mudd, Fulvio Reggiori, Vojo Deretic.
      Canonical autophagy is an intracellular pathway that degrades and recycles cellular components. A key step of this pathway is the formation of double-membraned organelles, known as autophagosomes, an emblematic feature of macroautophagy. For convenience, the formation of autophagosomes can be categorized into sequential steps, initiation (X), expansion (Y) and closure (Z). ATG9A is an integral membrane protein known for its role in the X and Y steps. whereby it organizes phagophore membrane assembly and its growth. Here, we report a previously unappreciated function of mammalian ATG9A in directing the last step Z. In particular, ATG9A partners with the key ESCRT-III component CHMP2A through IQGAP1 to facilitate autophagosome closure. Thus, ATG9A orchestrates all stages of autophagosome membrane biogenesis, from phagophore initiation to its closure. This makes ATG9A a unique ATG factor that works as a central hub in autophagosome biogenesis.
    Keywords:  Autophagy; ESCRT; IQGAP; closure; mitophagy; phagophore; tuberculosis
    DOI:  https://doi.org/10.1080/15548627.2025.2494802
  6. Virol J. 2025 Apr 17. 22(1): 103
    Usutu virus NS4A induces autophagy and is targeted by the selective autophagy receptor p62/SQSTM1 for degradation.
    Tessa Nelemans, Ali Tas, Nina L de Beijer, George M C Janssen, Peter A van Veelen, Martijn J van Hemert, Marjolein Kikkert.
      Usutu virus (USUV) is an emerging orthoflavivirus, which mainly affects birds but in rare cases can cause severe neuroinvasive disease in humans. The virus relies on a multitude of host cell proteins, molecules and cellular processes for its replication, and must subvert host antiviral responses to establish a successful infection. Studying the complex network of virus-host protein interactions by proteomics approaches can therefore provide new insights in the replication cycle of USUV and its pathogenesis. We have previously shown that the USUV protein NS4A acts as an antagonist of the antiviral interferon response, and here we further map the host interaction partners of USUV NS4A using proximity labeling coupled to mass spectrometry. The resulting NS4A interactome revealed many host proteins involved in the autophagy pathway. We showed that both USUV infection and overexpression of USUV NS4A can indeed induce the autophagy pathway. However, stimulation or inhibition of the autophagy pathway in general did not affect USUV replication. Therefore, we decided to specifically analyze the role of the selective autophagy receptor sequestosome 1 (p62/SQSTM1), since we identified this protein as an important interaction partner of USUV NS4A. We found that p62 is involved in the degradation of USUV NS4A. In agreement with this, the knockdown of p62 enhanced replication of USUV in A549 cells. P62 thus plays an antiviral role during USUV infection, although this antiviral effect might also be related to its functions outside the autophagy pathway, such as modulation of the immune response. In conclusion, this study showed that USUV NS4A induces autophagy and is then targeted by p62 for degradation by the autophagic machinery, uncovering a new role of p62 in the antiviral defense against USUV.
    Keywords:  Autophagy; NS4A; Orthoflavivirus; SQSTM1; Usutu virus; p62
    DOI:  https://doi.org/10.1186/s12985-025-02719-5
  7. Tohoku J Exp Med. 2025 Apr 17.
    FGF21 Activates Autophagy to Ameliorate Lipid Accumulation in NAFLD.
    Xuexin Xu, Jiayin Ren, Cuili Gong.
      
    DOI:  https://doi.org/10.1620/tjem.2025.J044
  8. Sci Adv. 2025 Apr 18. 11(16): eads1842
    Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging.
    Kristina Bubb, Julia Etich, Kristina Probst, Tanvi Parashar, Maximilian Schuetter, Frederik Dethloff, Susanna Reincke, Janica L Nolte, Marcus Krüger, Ursula Schlötzer-Schrehard, Julian Nüchel, Constantinos Demetriades, Patrick Giavalisco, Jan Riemer, Bent Brachvogel.
      Decline of mitochondrial respiratory chain (mtRC) capacity is a hallmark of mitochondrial diseases. Patients with mtRC dysfunction often present reduced skeletal growth as a sign of premature cartilage degeneration and aging, but how metabolic adaptations contribute to this phenotype is poorly understood. Here we show that, in mice with impaired mtRC in cartilage, reductive/reverse TCA cycle segments are activated to produce metabolite-derived amino acids and stimulate biosynthesis processes by mechanistic target of rapamycin complex 1 (mTORC1) activation during a period of massive skeletal growth and biomass production. However, chronic hyperactivation of mTORC1 suppresses autophagy-mediated organelle recycling and disturbs extracellular matrix secretion to trigger chondrocytes death, which is ameliorated by targeting the reductive metabolism. These findings explain how a primarily beneficial metabolic adaptation response required to counterbalance the loss of mtRC function, eventually translates into profound cell death and cartilage tissue degeneration. The knowledge of these dysregulated key nutrient signaling pathways can be used to target skeletal aging in mitochondrial disease.
    DOI:  https://doi.org/10.1126/sciadv.ads1842
  9. Cell Death Dis. 2025 Apr 15. 16(1): 300
    A variant of the autophagic receptor NDP52 counteracts phospho-TAU accumulation and emerges as a protective factor for Alzheimer's disease.
    Anna Mattioni, Claudia Carsetti, Krenare Bruqi, Valerio Caputo, Valentina Cianfanelli, Maria Giulia Bacalini, Mariella Casa, Carlo Gabelli, Emiliano Giardina, Gianluca Cestra, Flavie Strappazzon.
      Selective elimination of early pathological TAU species may be a promising therapeutic strategy to reduce the accumulation of TAU, which contributes to neurodegeneration and is a hallmark of Alzheimer's disease (AD). Pathological hyper-phosphorylated TAU can be degraded through selective autophagy, and NDP52/CALCOCO2 is one of the autophagy receptors involved in this process. In 2021, we discovered a variant of NDP52, called NDP52GE (rs550510), that is more efficient at promoting autophagy. We here anticipate that this variant could be a powerful factor that could eliminate pathological forms of TAU better than its WT form (NDP52WT). Indeed, we provide evidence that in in vitro systems and in a Drosophila melanogaster model of TAU-induced AD, the NDP52GE variant is much more effective than the NDP52WT in reducing the accumulation of pathological forms of TAU through the autophagic process and rescues typical neurodegenerative phenotypes induced by hTAU toxicity. Mechanistically, we showed that NDP52WT and NDP52GE bind pTAU with comparable efficiency, but that NDP52GE binds the autophagic machinery (LC3C and LC3B) more efficiently than NDP52WT does, which could explain its greater efficiency in removing pTAU. Finally, by performing a genetic analysis of a cohort of 435 AD patients, we defined the NDP52GE variant as a protective factor for AD. Overall, our work highlights the variant NDP52GE as a resilience factor in AD that shows a robust effectiveness in driving pathological TAU degradation.
    DOI:  https://doi.org/10.1038/s41419-025-07611-2
  10. Cell Rep. 2025 Apr 16. pii: S2211-1247(25)00370-5. [Epub ahead of print]44(5): 115599
    RabGAP1L modulates Rab7A and Rab10 to orchestrate cell-autonomous immunity.
    Atsuko Minowa-Nozawa, Takashi Nozawa, Kazunori Murase, Ichiro Nakagawa.
      Cell-autonomous immunity protects cells by utilizing membrane trafficking to detect and counteract diverse microbial pathogens, including selective autophagy and extracellular expulsion. However, the mechanisms underlying the mutual regulation among these systems has remained unknown. Here, we demonstrate that Rab GTPase-activating protein 1-like (RabGAP1L) modulates cell-autonomous immune responses via inactivation of two distinct Rab GTPases during group A Streptococcus (GAS) infection. Confocal microscopy analyses revealed that Rab7A positively regulates selective autophagy induction against GAS by facilitating endolysosomal trafficking and that Rab7A and Rab10 negatively regulate GAS expulsion from infected cells by inhibiting Rab11A-positive recycling endosome formation. RabGAP1L suppressed these pathways via inactivation of Rab7A and Rab10. By contrast, ATG7 and ATG5 knockout, resulting in autophagy deficiency, increased RabGAP1L-dependent bacterial expulsion from infected cells via the endocytic recycling pathway. Our findings suggest a regulatory mechanism of cell-autonomous immunity mediated by RabGAP1L, which contributes to the efficient elimination of intracellular pathogens.
    Keywords:  CP: Cell biology; CP: Immunology; Rab10; Rab7A; RabGAP1L; cell-autonomous immunity; extracellular expulsion; group A Streptococcus; selective autophagy
    DOI:  https://doi.org/10.1016/j.celrep.2025.115599
  11. Cell Death Dis. 2025 Apr 15. 16(1): 304
    Hepatitis B surface antigen hijacks TANK-binding kinase 1 to suppress type I interferon and induce early autophagy.
    Chuanjin Luo, Caijiao Ma, Gang Xu, Chengbo Lu, June Ma, Yu Huang, Longyu Nie, Chen Yu, Yongfang Xia, Zhiqiang Liu, Ying Zhu, Shi Liu.
      There are close links between innate immunity and autophagy. However, the crosstalk between innate immunity and autophagy in host cells infected with hepatitis B virus (HBV) remains unclear. Here, we reported that HBsAg suppressed type I interferon production and induced the accumulation of autophagosomes. HBsAg boosted TANK-binding kinase 1 (TBK1) phosphorylation and depressed interferon regulatory factor 3 (IRF3) phosphorylation ex vivo and in vivo. Mechanistic studies showed that HBsAg interaction with the kinase domain (KD) of TBK1 augmented its dimerization but disrupted TBK1-IRF3 complexes. Using the TBK1 inhibitor, BX795, we discovered that HBsAg-enhanced TBK1 dimerization, promoting sequestosome-1 (p62) phosphorylation, was necessary for HBV-induced autophagy and HBV replication. Moreover, HBsAg blocked autophagosome-lysosome fusion by inhibiting the synaptosomal-associated protein 29 (SNAP29) promoter. Notably, liver tissues from HBsAg transgenic mice or chronic HBV patients revealed that IFNβ signaling was inhibited and incomplete autophagy was induced. These findings suggest a novel mechanism by which HBsAg targets TBK1 to inhibit type I interferon and induce early autophagy, possibly leading to persistent HBV infection. Molecular mechanisms of HBsAg suppression of the IFNβ signaling pathway and triggering of early autophagy. HBsAg targets the kinase domain of TBK1, thereby disrupting the TBK1-IRF3 complex and inhibiting type I interferon production. On the other hand, HBsAg enhances TBK1 dimerization and phosphorylation, which upregulates the phosphorylation of p62 to induce p62-mediated autophagy. Furthermore, HBV infection causes the accumulation of autophagosomes. This is achieved by HBsAg suppressing the SNAP29 promoter activity, which blocks autophagosome-lysosome fusion.
    DOI:  https://doi.org/10.1038/s41419-025-07605-0
  12. Int Arch Allergy Immunol. 2025 Apr 12. 1-19
    Research progress of autophagy in the pathogenesis of bronchial asthma.
    Jing Huang, Rong-Hao Zhu, Fen-Hong Qian.
      Asthma is a complex chronic inflammatory disease of the airways characterized by chronic airway inflammation, hyperreactivity, and remodeling. Autophagy is responsible for lysosomal degradation through intracellular degradation when the proteasome cannot destroy damaged cytoplasmic organelles and proteins. Plenty of studies have shown that both impaired and overactive autophagic processes concern the pathogenesis of cancers, neurodegenerative diseases, metabolically associated diseases, and immune system diseases. Autophagy also plays both protective and damaging roles in the pathogenesis of asthma. To better understand the pathogenesis of asthma, this review will concentrate on the roles that autophagy plays in airway inflammation, immunological response, and remodeling. It will cover new advances and potential therapies on the role of autophagy in the onset and development of human asthma. This will contribute to the strategy for developing new targets to treat this disease.
    DOI:  https://doi.org/10.1159/000545456
  13. Int J Mol Sci. 2025 Apr 01. pii: 3252. [Epub ahead of print]26(7):
    Autophagy and Its Association with Macrophages in Clonal Hematopoiesis Leading to Atherosclerosis.
    Shuanhu Li, Xin Zhou, Qinchun Duan, Shukun Niu, Pengquan Li, Yihan Feng, Ye Zhang, Xuehong Xu, Shou-Ping Gong, Huiling Cao.
      Atherosclerosis, a chronic inflammatory disease characterized by lipid accumulation and immune cell infiltration, is linked to plaque formation and cardiovascular events. While traditionally associated with lipid metabolism and endothelial dysfunction, recent research highlights the roles of autophagy and clonal hematopoiesis (CH) in its pathogenesis. Autophagy, a cellular process crucial for degrading damaged components, regulates macrophage homeostasis and inflammation, both of which are pivotal in atherosclerosis. In macrophages, autophagy influences lipid metabolism, cytokine regulation, and oxidative stress, helping to prevent plaque instability. Defective autophagy exacerbates inflammation, impairs cholesterol efflux, and accelerates disease progression. Additionally, autophagic processes in endothelial cells and smooth muscle cells further contribute to atherosclerotic pathology. Recent studies also emphasize the interplay between autophagy and CH, wherein somatic mutations in genes like TET2, JAK2, and DNMT3A drive immune cell expansion and enhance inflammatory responses in atherosclerotic plaques. These mutations modify macrophage function, intensifying the inflammatory environment and accelerating atherosclerosis. Chaperone-mediated autophagy (CMA), a selective form of autophagy, also plays a critical role in regulating macrophage inflammation by degrading pro-inflammatory cytokines and oxidized low-density lipoprotein (ox-LDL). Impaired CMA activity leads to the accumulation of these substrates, activating the NLRP3 inflammasome and worsening inflammation. Preclinical studies suggest that pharmacologically activating CMA may mitigate atherosclerosis progression. In animal models, reduced CMA activity accelerates plaque instability and increases inflammation. This review highlights the importance of autophagic regulation in macrophages, focusing on its role in inflammation, plaque formation, and the contributions of CH. Building upon current advances, we propose a hypothesis in which autophagy, programmed cell death, and clonal hematopoiesis form a critical intrinsic axis that modulates the fundamental functions of macrophages, playing a complex role in the development of atherosclerosis. Understanding these mechanisms offers potential therapeutic strategies targeting autophagy and inflammation to reduce the burden of atherosclerotic cardiovascular disease.
    Keywords:  atherosclerosis; chaperone-mediated autophagy (CMA); clonal hematopoiesis (CH); inflammatory; macrophage; programmed cell death
    DOI:  https://doi.org/10.3390/ijms26073252
  14. Sci Adv. 2025 Apr 18. 11(16): eadt4881
    Sustained mTORC1 activation in activated T cells impairs vaccine responses in older individuals.
    Xiaorong Lin, Yanhua Du, Shuo Kan, Junjie Chen, Yunxue Yin, Linlin Li, Jingwen Chen, Wenrong Jiang, Wenqiang Cao, Chulwoo Kim, Liang Chen, Shiwen Wang, Jorg J Goronzy, Jun Jin.
      T cell aging contributes to the lower vaccine efficacy in older adults, yet the molecular mechanism remains elusive. Here, we show the density of initially responding naïve CD4+ T cells is instructive in T follicular helper (TFH) cell fate decisions and declines with age. A lower number of initially responding cells did not affect TFH differentiation at peak responses after immunization but accounted for an increased contraction phase manifesting as a larger loss of CXCR5 expression. Mechanistically, cells activated at a lower initial density had more sustained mammalian target of rapamycin complex 1 (mTORC1) activities that impair CXCR5 maintenance. YAP-dependent regulation of SLC7A5 involved in the cell density-dependent regulation of mTORC1 activities and TFH loss. Old mice fed with a leucine-restricted diet after peak responses showed smaller TFH loss and improved humoral immune responses. Attenuating mTORC1 signaling after peak response is a strategy to boost vaccine responses in older individuals.
    DOI:  https://doi.org/10.1126/sciadv.adt4881
  15. Mol Neurobiol. 2025 Apr 15.
    Upregulating mTOR/S6 K Pathway by CASTOR1 Promotes Astrocyte Proliferation and Myelination in Gpam-/--induced mouse model of cerebral palsy.
    Zhaofang Chen, Liru Liu, Xiaolin Guo, Yage Zhang, Mengru Zhong, Yi Xu, Tingting Peng, Tingting Peng, Yuan Zhang, Qingfen Hou, Danxia Fan, Ting Gao, Lu He, Hongmei Tang, Hao Hu, Kaishou Xu.
      GPAM, a key enzyme for lipid synthesis, is predominantly expressed in astrocytes (ASTs), where it facilitates lipid supply for myelin formation. Our previous studies identified GPAM as a novel causative gene for cerebral palsy (CP) and led to the development of a CP mouse model with GPAM deficiency (Gpam-/-). The model closely recapitulated the clinical phenotype of children with CP, due to the restricted proliferation of ASTs in the brain, reduced the amount of lipid, thinner brain white matter, and myelin dysplasia. The mammalian target of rapamycin (mTOR) pathway plays an important role in cell proliferation and lipid synthesis. Cytosolic arginine sensor (CASTOR1) interacts with GATOR2 to regulate mTOR complex 1 (mTORC1). Targeted degradation of CASTOR1 can activate the mTOR pathway. However, it remains unclear the involvement of mTOR pathway in neurological diseases such as CP. In this study, we demonstrated that the mTOR pathway was inhibited in Gpam-/- mice. Notably, CASTOR1 could regulate the activity of mTOR/S6K pathway, functioning as a negative upstream regulator. Furthermore, inhibition of CASTOR1 upregulated mTOR/S6K signaling, promoting astrocyte proliferation and myelination, which in turn enhanced motor function in the Gpam-/--induced CP mouse model. Collectively, these findings reveal the role of astrocytic mTOR in the pathogenesis of CP mice, broaden the therapeutic strategies, and provide a promising candidate target for CP treatment.
    Keywords:  Astrocyte; Cerebral palsy; Genetic animal mode; MTOR/S6 K; Motor ability; Myelination
    DOI:  https://doi.org/10.1007/s12035-025-04901-w
  16. Mol Med Rep. 2025 Jul;pii: 172. [Epub ahead of print]32(1):
    The role of Bcl‑2 in controlling the transition between autophagy and apoptosis (Review).
    Ahmet Alperen Palabiyik.
      The Bcl‑2 protein family serves a key role in maintaining cellular homeostasis by regulating the balance between autophagy and apoptosis. The present review aimed to summarize interactions of Bcl‑2 with key proteins, including Beclin 1, Bax and Bcl‑2 homologous antagonist/killer, as well as its influence on cellular processes such as mitophagy, nutrient sensing and endoplasmic reticulum stress response. The impact of post‑translational modifications of Bcl‑2, including phosphorylation, ubiquitination and sumoylation, is discussed with respect to their regulatory roles under stress. In pathological states, Bcl‑2 upregulation in cancer suppresses apoptosis and autophagy, thereby facilitating tumor survival and resistance to chemotherapy. Conversely, in neurodegenerative diseases, impaired autophagy and increased apoptosis contribute to neuronal loss. Therapeutic strategies targeting Bcl‑2 (for example inhibitors such as venetoclax, navitoclax, obatoclax and combination therapies involving autophagy modulators) were evaluated for their potential efficacy. There is lack of understanding of tissue‑specific functions of Bcl‑2 and its interactions with non‑coding RNAs. Future research should prioritize these areas and leverage advanced single‑cell technologies to elucidate the real‑time dynamics of Bcl‑2 in cell processes. The present review highlights the key role of Bcl‑2 in cell fate determination and highlights its potential as a therapeutic target, offering insight for the development of innovative treatments for cancer, neurodegenerative disorder and age‑related diseases.
    Keywords:  Bcl‑2; Beclin 1; apoptosis; autophagy; mitophagy
    DOI:  https://doi.org/10.3892/mmr.2025.13537
  17. Front Immunol. 2025 ;16 1528230
    The role of autophagy in cancer: from molecular mechanism to therapeutic window.
    Pooya Jalali, Arvin Shahmoradi, Amir Samii, Radman Mazloomnejad, Mohammad Reza Hatamnejad, Anwaar Saeed, Afshin Namdar, Zahra Salehi.
      Autophagy is a cellular degradation process that plays a crucial role in maintaining metabolic homeostasis under conditions of stress or nutrient deprivation. This process involves sequestering, breaking down, and recycling intracellular components such as proteins, organelles, and cytoplasmic materials. Autophagy also serves as a mechanism for eliminating pathogens and engulfing apoptotic cells. In the absence of stress, baseline autophagy activity is essential for degrading damaged cellular components and recycling nutrients to maintain cellular vitality. The relationship between autophagy and cancer is well-established; however, the biphasic nature of autophagy, acting as either a tumor growth inhibitor or promoter, has raised concerns regarding the regulation of tumorigenesis without inadvertently activating harmful aspects of autophagy. Consequently, elucidating the mechanisms by which autophagy contributes to cancer pathogenesis and the factors determining its pro- or anti-tumor effects is vital for devising effective therapeutic strategies. Furthermore, precision medicine approaches that tailor interventions to individual patients may enhance the efficacy of autophagy-related cancer treatments. To this end, interventions aimed at modulating the fate of tumor cells by controlling or inducing autophagy substrates necessitate meticulous monitoring of these mediators' functions within the tumor microenvironment to make informed decisions regarding their activation or inactivation. This review provides an updated perspective on the roles of autophagy in cancer, and discusses the potential challenges associated with autophagy-related cancer treatment. The article also highlights currently available strategies and identifies questions that require further investigation in the future.
    Keywords:  autophagy; cancer; immunotherapy; precision-medicine; tumorigenesis
    DOI:  https://doi.org/10.3389/fimmu.2025.1528230
  18. Mol Psychiatry. 2025 Apr 17.
    Animal studies reveal downregulation of the Beclin-1 autophagy pathway as shared mechanism in Autism Spectrum Disorder: a systematic review and meta-analysis.
    A Abromeit, C R Hooijmans, C LeMaoult, C M Drion, Mjh Kas.
       BACKGROUND: Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition with complex etiology, involving genetic and environmental influences on brain development and behavior. Dysregulation of mammalian target of rapamycin (mTOR) signaling alters neuronal growth and synaptic plasticity, and has emerged as a potential underlying pathway in ASD.
    GOAL AND METHODS: To investigate mTOR dysregulation as a common mechanism in ASD, we performed a systematic review, and a meta-analysis of 192 studies examining mTOR signaling in diverse genetic and environmental animal models.
    RESULTS: Our random-effects model identified significant alterations in mTOR pathway-related proteins. For several proteins (p-AKT, PTEN, p-mTOR, p-EIF4e, LC3-II, p-S6K and p-S6), subgroup analyses revealed clear species-, sex-, age-, or brain region-specific effects. Interestingly, Beclin-1 was consistently downregulated across all subgroups.
    CONCLUSION: Our findings support mTOR-pathway dysregulation in ASD. The observed consistent downregulation of Beclin-1 highlights autophagy as a common mechanism, and provides new leads for novel ASD biomarker and treatment development.
    DOI:  https://doi.org/10.1038/s41380-025-03028-7
  19. Cell Death Discov. 2025 Apr 16. 11(1): 181
    Identification of new candidates regulating autophagy-dependent midgut degradation in Drosophila melanogaster.
    Ruchi Umargamwala, Shannon Nicolson, Jantina Manning, Julian M Carosi, Sharad Kumar, Donna Denton.
      Autophagy-dependent cell death (ADCD) is a context-specific form of programmed cell death that plays an important role in development and homeostasis. During Drosophila metamorphosis, hormonal cues modulate growth and other signalling cascades which results in autophagy-dependent degradation of the obsolete larval midgut. While this process does not require caspase activity or apoptotic machinery, several canonical autophagy-related proteins are also dispensable, suggesting additional regulators may be involved in effectively eliminating the larval midgut. Ubiquitination, a process that attaches one or more ubiquitin moieties to a substrate through sequential reactions involving a cascade of enzymes, plays a critical role in autophagy. As the specific role(s) of ubiquitination in ADCD has not been explored, we previously performed a RNAi-mediated knockdown screen of over 250 ubiquitin machinery genes in GFP-labelled Drosophila larval midguts and identified 18 candidate regulators of midgut degradation. In this work, we screened candidate genes for a role in autophagy-dependent midgut degradation by analysing mosaic clones and genetic interactions with Atg1. Validation and further studies into the ubiquitin conjugating enzyme, Effete (Eff), and two ubiquitin ligases, Cullin-4 (Cul4) and Supernumerary limbs (Slmb), demonstrated interplay between ubiquitination and the autophagy machinery in coordinating autophagy-dependent midgut degradation.
    DOI:  https://doi.org/10.1038/s41420-025-02474-0
  20. Antioxidants (Basel). 2025 Feb 25. pii: 264. [Epub ahead of print]14(3):
    Crosstalk Between Autophagy and Oxidative Stress in Hematological Malignancies: Mechanisms, Implications, and Therapeutic Potential.
    Antonio José Cabrera-Serrano, José Manuel Sánchez-Maldonado, Carmen González-Olmedo, María Carretero-Fernández, Leticia Díaz-Beltrán, Juan Francisco Gutiérrez-Bautista, Francisco José García-Verdejo, Fernando Gálvez-Montosa, José Antonio López-López, Paloma García-Martín, Eva María Pérez, Pedro Sánchez-Rovira, Fernando Jesús Reyes-Zurita, Juan Sainz.
      Autophagy is a fundamental cellular process that maintains homeostasis by degrading damaged components and regulating stress responses. It plays a crucial role in cancer biology, including tumor progression, metastasis, and therapeutic resistance. Oxidative stress, similarly, is key to maintaining cellular balance by regulating oxidants and antioxidants, with its disruption leading to molecular damage. The interplay between autophagy and oxidative stress is particularly significant, as reactive oxygen species (ROS) act as both inducers and by-products of autophagy. While autophagy can function as a tumor suppressor in early cancer stages, it often shifts to a pro-tumorigenic role in advanced disease, aiding cancer cell survival under adverse conditions such as hypoxia and nutrient deprivation. This dual role is mediated by several signaling pathways, including PI3K/AKT/mTOR, AMPK, and HIF-1α, which coordinate the balance between autophagic activity and ROS production. In this review, we explore the mechanisms by which autophagy and oxidative stress interact across different hematological malignancies. We discuss how oxidative stress triggers autophagy, creating a feedback loop that promotes tumor survival, and how autophagic dysregulation leads to increased ROS accumulation, exacerbating tumorigenesis. We also examine the therapeutic implications of targeting the autophagy-oxidative stress axis in cancer. Current strategies involve modulating autophagy through specific inhibitors, enhancing ROS levels with pro-oxidant compounds, and combining these approaches with conventional therapies to overcome drug resistance. Understanding the complex relationship between autophagy and oxidative stress provides critical insights into novel therapeutic strategies aimed at improving cancer treatment outcomes.
    Keywords:  autophagy; cancer treatment outcomes; crosstalk; hematological malignancies; oxidative stress; reactive oxygen species; therapeutic opportunities
    DOI:  https://doi.org/10.3390/antiox14030264
  21. Antioxidants (Basel). 2025 Mar 13. pii: 339. [Epub ahead of print]14(3):
    The Interplay Between Autophagy and Apoptosis in the Mechanisms of Action of Stilbenes in Cancer Cells.
    Kamila Siedlecka-Kroplewska, Zbigniew Kmiec, Michal Aleksander Zmijewski.
      Plant-based stilbenes are low-molecular-weight polyphenolic compounds that exhibit anti-oxidant, anti-microbial, anti-fungal, anti-inflammatory, anti-diabetic, cardioprotective, neuroprotective, and anti-cancer activities. They are phytoalexins produced in diverse plant species in response to stress, such as fungal and bacterial infections or excessive UV irradiation. Plant-derived dietary products containing stilbenes are common components of the human diet. Stilbenes appear to be promising chemopreventive and chemotherapeutic agents. Accumulating evidence indicates that stilbenes are able to trigger both apoptotic and autophagic molecular pathways in many human cancer cell lines. Of note, the molecular crosstalk between autophagy and apoptosis under cellular stress conditions determines the cell fate. The autophagy and apoptosis relationship is complex and depends on the cellular context, e.g., cell type and cellular stress level. Apoptosis is a type of regulated cell death, whereas autophagy may act as a pro-survival or pro-death mechanism depending on the context. The interplay between autophagy and apoptosis may have an important impact on chemotherapy efficiency. This review focuses on the in vitro effects of stilbenes in different human cancer cell lines concerning the interplay between autophagy and apoptosis.
    Keywords:  apoptosis; autophagy; cancer cells; cell death; piceatannol; polyphenols; pterostilbene; resveratrol; stilbenes; stilbenoids
    DOI:  https://doi.org/10.3390/antiox14030339
  22. Mol Neurobiol. 2025 Apr 16.
    Mitophagy in Brain Injuries: Mechanisms, Roles, and Therapeutic Potential.
    Jiayu Tian, Yanna Mao, Dandan Liu, Tao Li, Yafeng Wang, Changlian Zhu.
      Mitophagy is an intracellular degradation pathway crucial for clearing damaged or dysfunctional mitochondria, thereby maintaining cellular homeostasis and responding to various brain injuries. By promptly removing damaged mitochondria, mitophagy protects cells from further harm and support cellular repair and recovery after injury. In different types of brain injury, mitophagy plays complex and critical roles, from regulating the balance between cell death and survival to influencing neurological recovery. This review aims to deeply explore the role and mechanism of mitophagy in the context of brain injuries and uncover how mitophagy regulates the brain response to injury and its potential therapeutic significance. It emphasizes mitophagy's potential in treating brain injuries, including reducing cell damage, promoting cell recovery, and improving neurological function, thus opening new perspectives and directions for future research and clinical applications.
    Keywords:  Brain injury; Cell death; Mitophagy; Mitophagy regulation; Therapeutic strategy
    DOI:  https://doi.org/10.1007/s12035-025-04936-z
  23. ACS Pharmacol Transl Sci. 2025 Apr 11. 8(4): 1140-1151
    PAC-1 Synergizes with Sunitinib to Enhance Cell Death in Pancreatic Neuroendocrine Tumors.
    Hyang Yeon Lee, Myung Ryul Lee, Timothy M Fan, Paul J Hergenrother.
      Pancreatic neuroendocrine tumors (PNETs) are rare tumors that are often diagnosed at advanced or metastatic stages, resulting in a poor prognosis. Sunitinib is an approved therapy for treatment of patients with PNETs, but low response rates and resistance have limited its impact, with autophagy and sunitinib sequestration in the lysosome identified as key resistance mechanisms. Here, we show that the combination of sunitinib with the procaspase-3 activator PAC-1 enhances PNET cell death in cell culture and in vivo in a xenograft tumor model. PAC-1 treatment enlarges lysosomes, resulting in partial lysosomal membrane permeabilization and blocking of autophagosome-lysosome fusion. These alterations lead to increased accumulation of autophagic structures, blocking autophagic flux, and a changed distribution of sunitinib from the lysosome to the cytosol. Our data show that PAC-1 modulates sunitinib-induced autophagy and blocks lysosomal trapping, potentiating sunitinib activity and increasing death of cancer cells. As both drugs are well-tolerated in patients, the data suggest evaluation of the PAC-1/sunitinib combination in a clinical trial of patients with PNET.
    DOI:  https://doi.org/10.1021/acsptsci.5c00052
  24. Int J Mol Sci. 2025 Mar 23. pii: 2905. [Epub ahead of print]26(7):
    The Spectrum of Small Heat Shock Protein B8 (HSPB8)-Associated Neuromuscular Disorders.
    Hebatallah R Rashed, Samir R Nath, Margherita Milone.
      The heat shock protein B8 (HSPB8) is one of the small heat shock proteins (sHSP or HSPB) and is a ubiquitous protein in various organisms, including humans. It is highly expressed in skeletal muscle, heart, and neurons. It plays a crucial role in identifying misfolding proteins and participating in chaperone-assisted selective autophagy (CASA) for the removal of misfolded and damaged, potentially cytotoxic proteins. Mutations in HSPB8 can cause distal hereditary motor neuropathy (dHMN), Charcot-Marie-Tooth (CMT) disease type 2L, or myopathy. The disease can manifest from childhood to mid-adulthood. Most missense mutations in the N-terminal and α-crystallin domains of HSPB8 lead to dHMN or CMT2L. Frameshift mutations in the C-terminal domain (CTD), resulting in elongation of the HSPB8 C-terminal, cause myopathy with myofibrillar pathology and rimmed vacuoles. Myopathy and motor neuropathy can coexist. HSPB8 frameshift mutations in the CTD result in HSPB8 mutant aggregation, which weakens the CASA ability to direct misfolded proteins to autophagic degradation. Cellular and animal models indicate that HSPB8 mutations drive pathogenesis through a toxic gain-of-function mechanism. Currently, no cure is available for HSPB8-associated neuromuscular disorders, but numerous therapeutic strategies are under investigation spanning from small molecules to RNA interference to exogenous HSPB8 delivery.
    Keywords:  CASA; CMT2L; CTM2; HMN; HSPB8; dHMN; myofibrillar myopathy; myopathy; rimmed vacuoles
    DOI:  https://doi.org/10.3390/ijms26072905
  25. Nutrients. 2025 Mar 27. pii: 1158. [Epub ahead of print]17(7):
    N6-Methyladenosine Modification in the Metabolic Dysfunction-Associated Steatotic Liver Disease.
    Satoru Matsuda, Moeka Nakashima, Akari Fukumoto, Naoko Suga.
      Epigenetics of N6-methyladenine (m6A) modification may play a key role during the regulation of various diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). The m6A modification has been shown to be accomplished via the exploitation of several players such as methyltransferases, demethylases, and/or methylation-binding molecules. Significantly, the m6A methylation can regulate the key eukaryotic transcriptome by affecting the subcellular localization, splicing, export, stability, translation, and decay of those RNAs. An increasing amount of data has designated that the m6A modification of RNAs can also modulate the expression of autophagy-related genes, which could also control the autophagy in hepatocytes. Oxidative stress with reactive oxygen species (ROS) can induce m6A RNA methylation, which might be associated with the regulation of mitochondrial autophagy (mitophagy) and/or the development of MASLD. Therefore, both autophagy and the m6A modification could play important roles in regulating the pathogenesis of MASLD. Comprehending the relationship between m6A and mitophagy may be helpful for the development of future therapeutic strategies against MASLD. This review would advance the understanding of the regulatory mechanisms of m6A RNA modification, focusing on the impact of mitochondrial dysregulation and mitophagy in the liver with MASLD.
    Keywords:  MASLD; N6-methyladenine; RNA binding protein; autophagy; liver dysfunction; mitophagy; non-coding RNA; reactive oxygen species
    DOI:  https://doi.org/10.3390/nu17071158
  26. Sci Rep. 2025 Apr 17. 15(1): 13234
    CYB5A promotes osteogenic differentiation of MC3T3-E1 cells through autophagy mediated by the AKT/mTOR/ULK1 signaling pathway.
    Yanjie Zhang, Jinmeng Li, Beibei Liu, Peilin Wang, Hanyu Xiao, Qingfu Wang, Ruixin Li, Jian Zhang.
      Bone metabolism involves complex genetic and cellular processes. While many advances have been made in understanding the molecular mechanisms of osteogenic differentiation, many aspects remain to be fully elucidated. This study investigated the role of CYB5A in promoting osteogenic differentiation of MC3T3-E1 cells and explored the influence of autophagy via the AKT/mTOR/ULK1 signaling pathway. CYB5A expression during osteogenesis was analyzed through bioinformatics, quantitative reverse transcription polymerase chain reaction, and Western blotting. CYB5A was overexpressed or knocked down via plasmid or small interfering RNA transfection, and its effects on cell proliferation, migration, and differentiation were evaluated. Results showed that CYB5A expression increased during differentiation without affecting proliferation. However, CYB5A significantly enhanced cell differentiation by stimulating autophagy, as indicated by an increased ratio of the autophagic marker LC3-II/LC3-I and reduced levels of P62. Mechanistically, CYB5A modulates autophagy by activating ULK1 and reducing active mTOR phosphorylation. Autophagy inhibitors and activators confirmed that the AKT/mTOR/ULK1 pathway mediates CYB5A's regulatory effects on osteogenesis. This study reveals that CYB5A positively regulates osteogenic differentiation through autophagy, offering insights into bone metabolism mechanisms. These findings suggest that CYB5A is a promising therapeutic target for managing bone metabolic disorders.
    Keywords:  Autophagy; Bone disorder; CYB5A; Osteogenic differentiation
    DOI:  https://doi.org/10.1038/s41598-025-97086-0
  27. Biomaterials. 2025 Apr 15. pii: S0142-9612(25)00264-9. [Epub ahead of print]321 123345
    A ROS-Responsive nanoparticle for nuclear gene delivery and autophagy restoration in Parkinson's disease therapy.
    Limin Zhai, Yifei Gao, Hao Yang, Haoyuan Wang, Beining Liao, Yuxue Cheng, Chao Liu, Jingfeng Che, Kunwen Xia, Lingkun Zhang, Yanqing Guan.
      Parkinson's disease (PD) is characterized by the pathological aggregation of α-synuclein (α-syn) and neuroinflammation. Current gene therapies face challenges in nuclear delivery and resolving pre-existing α-syn aggregates. Here, we developed glucose-and trehalose-functionalized carbonized polymer dots (GT-PCDs) loaded with plasmid DNA (pDNA) for targeted gene delivery and autophagy restoration. The GT-PCDs@pDNA nanoparticles exhibit reactive oxygen species (ROS)-responsive behavior, enabling efficient nuclear entry under oxidative stress conditions. Both in vitro and in vivo studies demonstrated that GT-PCDs@pDNA effectively silenced SNCA gene expression, reduced α-syn aggregates, and restored autophagic flux by promoting transcription factor EB (TFEB) nuclear translocation. Moreover, GT-PCDs@pDNA enhanced blood-brain barrier (BBB) permeability via glucose transporter 1 (Glut-1)-mediated transcytosis, significantly improving motor deficits and reducing neuroinflammation in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. This multifunctional nanocarrier system offers a promising strategy for combined gene therapy and autophagy modulation in neurodegenerative diseases.
    Keywords:  Autophagy; Nuclear gene delivery; Parkinson's disease; ROS response; α-synuclein
    DOI:  https://doi.org/10.1016/j.biomaterials.2025.123345
  28. Int J Mol Sci. 2025 Mar 21. pii: 2867. [Epub ahead of print]26(7):
    Lysosomal Dysfunction in Amyotrophic Lateral Sclerosis: A Familial Case Linked to the p.G376D TARDBP Mutation.
    Roberta Romano, Victoria Stefania Del Fiore, Giorgia Ruotolo, Martina Mazzoni, Jessica Rosati, Francesca Luisa Conforti, Cecilia Bucci.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Consequent to the loss of these cells, neuromuscular functions decline, causing progressive weakness, muscle wasting, and paralysis, leading to death in 2 to 5 years. More than 90% of ALS cases are sporadic, while the remaining 10% of cases are familial, due to mutations in 40 different genes. One of the most common genes to be mutated in ALS is TARDBP (transactive response DNA binding protein 43), which encodes TDP-43 (TAR DNA-binding protein 43). A mutation in exon 6 of TARDBP causes the aminoacidic substitution G376D in the C-terminal region of TDP-43, leading to its cytoplasmic mislocalization and aggregation. In fibroblasts derived from patients carrying this mutation, we found a strong increase in lysosome number, with overexpression and higher nuclear translocation of the transcription factor TFEB. In contrast, lysosomal functionality was deeply compromised. Interestingly, lysosomal activity was unaffected at an early stage of the disease, worsening in more advanced stages. Moreover, we observed the same pathological phenotype in iPSC (induced pluripotent stem cells)-derived patient motor neurons carrying the G376D mutation. Therefore, this mutation compromises the functionality of lysosomes, possibly contributing to neurodegeneration.
    Keywords:  TDP-43; TFEB; amyotrophic lateral sclerosis; lysosome; neurodegeneration; neurodegenerative disease
    DOI:  https://doi.org/10.3390/ijms26072867
  29. Stem Cell Res Ther. 2025 Apr 15. 16(1): 180
    Mitochondrial quality control in hematopoietic stem cells: mechanisms, implications, and therapeutic opportunities.
    Yun Liao, Stacia Octaviani, Zhen Tian, Samuel R Wang, Chunlan Huang, Jian Huang.
      Mitochondrial quality control (MQC) is a critical mechanism for maintaining mitochondrial function and cellular metabolic homeostasis, playing an essential role in the self-renewal, differentiation, and long-term stability of hematopoietic stem cells (HSCs). Recent research highlights the central importance of MQC in HSC biology, particularly the roles of mitophagy, mitochondrial biogenesis, fission, fusion and mitochondrial transfer in regulating HSC function. Mitophagy ensures the removal of damaged mitochondria, maintaining low levels of reactive oxygen species (ROS) in HSCs, thereby preventing premature aging and functional decline. Concurrently, mitochondrial biogenesis adjusts key metabolic regulators such as mitochondrial transcription factor A (TFAM) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) to meet environmental demands, ensuring the metabolic needs of HSCs are met. Additionally, mitochondrial transfer, as an essential form of intercellular material exchange, facilitates the transfer of functional mitochondria from bone marrow stromal cells to HSCs, contributing to damage repair and metabolic support. Although existing studies have revealed the significance of MQC in maintaining HSC function, the precise molecular mechanisms and interactions among different regulatory pathways remain to be fully elucidated. Furthermore, the potential role of MQC dysfunction in hematopoietic disorders, including its involvement in disease progression and therapeutic resistance, is not yet fully understood. This review discusses the molecular mechanisms of MQC in HSCs, its functions under physiological and pathological conditions, and its potential therapeutic applications. By summarizing the current progress in this field, we aim to provide insights for further research and the development of innovative treatment strategies.
    Keywords:  Hematopoietic stem cell; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial metabolism; Mitochondrial quality control; Mitochondrial transfer; Mitophagy
    DOI:  https://doi.org/10.1186/s13287-025-04304-7
  30. Int Immunopharmacol. 2025 Apr 11. pii: S1567-5769(25)00633-2. [Epub ahead of print]155 114643
    Immunomodulatory roles of autophagic flux and IFIT in human ectocervical cells upon Trichomonas vaginalis infection.
    Ching-Chun Liu, Lichieh Julie Chu, Yuan-Ming Yeh, Hsin-Chung Lin, Lih-Chyang Chen, Ching-Yun Huang, Shu-Fang Chiu, Fang-Wen Cheng, Wei-Ning Lin, Kuo-Yang Huang.
      Trichomonas vaginalis (Tv) is the causative agent of trichomoniasis, the most common non-viral sexually transmitted infection worldwide. Despite its high prevalence, the mechanisms underlying Tv-induced inflammatory responses remain poorly understood. Herein, we investigated the signaling pathways mediating Tv-induced inflammation in ectocervical cells (Ects). We initially measured the production of various cytokines using a multiplex immunoassay, revealing a significant increase in IL-6, IL-8, IP-10, and CXCL1 secretion in Ects upon Tv infection. We then assessed the role of autophagy in regulating Tv-induced inflammation in Ects by using autophagy inhibitors and small interfering RNA targeting LC3B (si-LC3B) to block different stages of autophagy. Our findings indicated that Tv-induced autophagic flux mediates the secretion of proinflammatory cytokines in Ects. Additionally, blocking autophagosome formation via si-LC3B increases IL-6 and IP-10 levels while reducing IL-8 secretion. To further identify novel pathways involved in Tv-induced inflammation in Ects, we conducted a time-series proteomic analysis using 2D-LC-MS/MS. Intriguingly, we noticed robust activation of antiviral-related pathways in Ects after 8 h of Tv stimulation. Specifically, the most enriched proteins in these pathways were tetratricopeptide repeats (IFIT) family proteins (IFIT1, IFIT2, and IFIT3). Functional validation revealed that IFIT3 positively regulates downstream IL-8 and IP-10 secretion. Furthermore, we proved that si-LC3B enhanced IFIT expression in Ects upon Tv infection, suggesting that autophagy negatively regulates IFIT expression. Collectively, this study demonstrates that Tv infection induces autophagic flux and IFIT overexpression to modulate inflammatory responses in Ects, providing novel insights into the inflammatory mechanisms governing trichomoniasis.
    Keywords:  Autophagy; Ectocervical cells; IFIT; IP-10; Trichomonas vaginalis
    DOI:  https://doi.org/10.1016/j.intimp.2025.114643
  31. Int J Mol Sci. 2025 Mar 28. pii: 3154. [Epub ahead of print]26(7):
    Role of Extracellular Vesicles in TSC Renal Cystogenesis.
    Kamyar Zahedi, Mackenzie Morgan, Brenda Prieto, Marybeth Brooks, Tamara A Howard, Sharon Barone, John J Bissler, Christos Argyropoulos, Manoocher Soleimani.
      Tuberous sclerosis complex (TSC) is caused by mutations in TSC1 or TSC2 genes and affects multiple organs. TSC proteins control cell growth by regulating the activity of the mechanistic target of rapamycin complex 1. Extracellular vesicles (EVs) are membrane-bound particles produced by cells that mediate cellular communication, function, and growth. Although extensive studies regarding the genetic basis of TSC exist, the exact mechanism contributing to its pathogenesis remains unresolved. It has been proposed that EVs generated by renal cyst epithelia of mice and cells with Tsc gene mutations contain factors that alter the function and proliferation of TSC-sufficient cells. To test this, EVs from the kidneys and kidney explants of wildtype and Tsc1KO mice were isolated and characterized by Western blotting, transmission electron microscopy, dynamic light scattering, and fluorescent nanoparticle tracking. Our results show an enrichment in EV-associated markers and particle sizes of similar ranges. RNA-seq and proteomic analyses identified EV shuttle factors. EV RNA and protein shuttle factors showed significant differences. Furthermore, EVs isolated from Tsc1KO mice inhibited the proliferation of M-1 cells. Understanding the role of EVs in cell proliferation and cystogenesis in TSC may lead to the development of new approaches for the treatment of this disease.
    Keywords:  A-intercalated cells; collecting duct; cystogenesis; extracellular vesicles; kidney; principal cells; tuberous sclerosis complex
    DOI:  https://doi.org/10.3390/ijms26073154
  32. J Mol Biol. 2025 Apr 11. pii: S0022-2836(25)00217-7. [Epub ahead of print] 169151
    Autophagy, ER-phagy and ER dynamics during cell differentiation.
    Michele Cillo, Viviana Buonomo, Anna Vainshtein, Paolo Grumati.
      The endoplasmic reticulum (ER) is a multifunctional organelle essential for protein and lipid synthesis, ion transport and inter-organelle communication. It comprises a highly dynamic network of membranes that continuously reshape to support a wide range of cellular processes. During cellular differentiation, extensive remodelling of both ER architecture and its proteome is required to accommodate alterations in cell morphology and function. Autophagy, and ER-phagy in particular, plays a pivotal role in reshaping the ER, enabling cells to meet their evolving needs and adapt to developmental cues. Despite the ER's critical role in cellular differentiation, the mechanisms responsible for regulating its dynamics are not fully understood. Emerging evidence suggests that transcriptional and post-translational regulation play a role in fine-tuning ER-phagy and the unfolded protein response (UPR). This review explores the molecular basis of autophagy and ER-phagy, highlighting their role in ER remodelling during cellular differentiation. A deeper understanding of these processes could open new avenues for targeted therapeutic approaches in conditions where ER remodelling is impaired.
    Keywords:  Cell Differentiation; Development; Endoplasmic Reticulum
    DOI:  https://doi.org/10.1016/j.jmb.2025.169151
  33. Antioxidants (Basel). 2025 Feb 28. pii: 302. [Epub ahead of print]14(3):
    Roles of Oxidative Stress and Autophagy in Alcohol-Mediated Brain Damage.
    Leon Ruiter-Lopez, Mohammed A S Khan, Xin Wang, Byoung-Joon Song.
      Excessive alcohol consumption significantly impacts human health, particularly the brain, due to its susceptibility to oxidative stress, which contributes to neurodegenerative conditions. Alcohol metabolism in the brain occurs primarily via catalase, followed by CYP2E1 pathways. Excess alcohol metabolized by CYP2E1 generates reactive oxygen/nitrogen species (ROS/RNS), leading to cell injury via altering many different pathways. Elevated oxidative stress impairs autophagic processes, increasing post-translational modifications and further exacerbating mitochondrial dysfunction and ER stress, leading to cell death. The literature highlights that alcohol-induced oxidative stress disrupts autophagy and mitophagy, contributing to neuronal damage. Key mechanisms include mitochondrial dysfunction, ER stress, epigenetics, and the accumulation of oxidatively modified proteins, which lead to neuroinflammation and impaired cellular quality control. These processes are exacerbated by chronic alcohol exposure, resulting in the suppression of protective pathways like NRF2-mediated antioxidant responses and increased susceptibility to neurodegenerative changes in the brain. Alcohol-mediated neurotoxicity involves complex interactions between alcohol metabolism, oxidative stress, and autophagy regulation, which are influenced by various factors such as drinking patterns, nutritional status, and genetic/environmental factors, highlighting the need for further molecular studies to unravel these mechanisms and develop targeted interventions.
    Keywords:  alcohol metabolism; antioxidants; autophagy; brain; ethanol; mitophagy; neurodegeneration; neurotoxicity; oxidative stress
    DOI:  https://doi.org/10.3390/antiox14030302
  34. Am J Physiol Gastrointest Liver Physiol. 2025 Apr 17.
    Saturated Phosphatidic Acids Induce mTORC1-Driven Integrated Stress Response Contributing to Glucolipotoxicity in Hepatocytes.
    Rui Guo, Yanhui Li, Yuwei Jiang, Md Wasim Khan, Brian T Layden, Zhenyuan Song.
      Hepatic glucolipotoxicity, characterized by the synergistic detrimental effects of elevated glucose levels combined with excessive lipid accumulation in hepatocytes, plays a central role in the pathogenesis of various metabolic liver diseases. Despite recent advancements, the precise mechanisms underlying this process remain unclear. Employing cultured AML12 and HepG2 cells exposed to excess palmitate, with and without high glucose, as an in vitro model, we aimed to elucidate the cellular and molecular mechanisms underlying hepatic glucolipotoxicity. Our data showed that palmitate exposure induced the integrated stress response (ISR) in hepatocytes, evidenced by increased eIF2α phosphorylation (serine 51) and upregulated ATF4 expression. Moreover, we identified mTORC1 as a novel upstream kinase responsible for palmitate-triggered ISR induction. Furthermore, we showed that either mTORC1 inhibitors, ISRIB (an ISR inhibitor), or ATF4 knockdown abolished palmitate-induced cell death, indicating that the mTORC1-eIF2α- ATF4 pathway activation plays a mechanistic role in mediating palmitate-induced hepatocyte cell death. Our continuous investigations revealed that GPAT4-mediated metabolic flux of palmitate into the glycerolipid synthesis pathway is required for palmitate-induced mTORC1 activation and subsequent ISR induction. Specifically, we uncovered that saturated phosphatidic acid production contributes to palmitate-triggered mTORC1 activation. Our study provides the first evidence that high glucose enhances palmitate-induced activation of the mTORC1-eIF2α-ATF4 pathway, thereby exacerbating palmitate-induced hepatotoxicity. This effect is mediated by the increased availability of glycerol-3-phosphate, a substrate essential for phosphatidic acid synthesis. In conclusion, our study highlights that the activation of the mTORC1-eIF2α-ATF4 pathway, driven by saturated phosphatidic acid overproduction, plays a mechanistic role in hepatic glucolipotoxicity.
    Keywords:  ISR; Palmitate; glucolipotoxicity; mTORC1; phosphatidic acid
    DOI:  https://doi.org/10.1152/ajpgi.00027.2025
  35. Nat Chem Biol. 2025 Apr 17.
    Induced proximity to PML protects TDP-43 from aggregation via SUMO-ubiquitin networks.
    Kristina Wagner, Jan Keiten-Schmitz, Bikash Adhikari, Upayan Patra, Koraljka Husnjak, François McNicoll, Dorothee Dormann, Michaela Müller-McNicoll, Georg Tascher, Elmar Wolf, Stefan Müller.
      The established role of cytosolic and nuclear inclusions of TDP-43 in the pathogenesis of neurodegenerative disorders has multiplied efforts to understand mechanisms that control TDP-43 aggregation and has spurred searches for approaches limiting this process. Formation and clearance of TDP-43 aggregates are controlled by an intricate interplay of cellular proteostasis systems that involve post-translational modifications and frequently rely on spatial control. We demonstrate that attachment of the ubiquitin-like SUMO2 modifier compartmentalizes TDP-43 in promyelocytic leukemia protein (PML) nuclear bodies and limits the aggregation of TDP-43 in response to proteotoxic stress. Exploiting this pathway through proximity-inducing recruitment of TDP-43 to PML triggers a SUMOylation-ubiquitylation cascade protecting TDP-43 from stress-induced insolubility. The protective function of PML is mediated by ubiquitylation in conjunction with the p97 disaggregase. Altogether, we demonstrate that SUMO-ubiquitin networks protect cells from insoluble TDP-43 inclusions and propose the functionalization of PML as a potential future therapeutic avenue countering aggregation.
    DOI:  https://doi.org/10.1038/s41589-025-01886-4
  36. Int Immunopharmacol. 2025 Apr 15. pii: S1567-5769(25)00658-7. [Epub ahead of print]155 114668
    A novel mechanism of FBXW7 in combating intervertebral disc degeneration: Mitigating ferroptosis in nucleus pulposus cells through the regulation of mitophagy.
    Xiao Lu, Zhidi Lin, Dachuan Li, Zhaoyang Gong, Tiancong Ma, Jiongdong Wu, Wenbiao Xiao, Chenpei Xu, Yunzhi Guan, Shuo Yang, Yuxuan Zhang, Chi Sun, Xinlei Xia, Feizhou Lu, Jian Song, Jianyuan Jiang, Wei Zhu, Guangyu Xu, Xiaosheng Ma, Fei Zou.
      With the aging of the global population, the prevalence of intervertebral disc degeneration (IVDD) disease is gradually increasing. This disease not only leads to a substantial reduction in the quality of life of patients but also imposes a considerable burden on the health care system. At present, the understanding of its pathogenesis is relatively limited, and in-depth research is urgently needed to identify effective treatment methods. One of the main causes of IVDD is the compression of the spine caused by body weight. The objective of this study was to investigate the potential regulatory mechanism underlying IVDD induced by excessive compression. Moreover, to investigate whether FBXW7 is involved in the regulation of mitophagy and ferroptosis, we used 1 MPa pressure to induce nucleus pulposus cell (NPC) degeneration and then constructed plasmids or small interfering RNAs to overexpress or knock down FBXW7. In addition, in vivo animal experiments were performed to verify the function of FBXW7. We found that FBXW7 expression was decreased in degenerative NP tissues. Compression promoted the initiation of mitophagy, but blocked autophagic flux and ultimately caused ferroptosis in NPCs. However, overexpression of FBXW7 can activate mitophagy, improve autophagic flux, and alleviate ferroptosis. Moreover, FBXW7 can bind to mTOR and promote its ubiquitination and degradation, thus increasing the expression of PINK1 and Parkin. Taken together, the results of both in vitro and in vivo experiments suggested that FBXW7 induced mitophagy, alleviated ferroptosis, and delayed IVDD via the mTOR signaling pathway.
    Keywords:  FBXW7; Ferroptosis; Intervertebral disc degeneration; Mitophagy; Nucleus pulposus; mTOR
    DOI:  https://doi.org/10.1016/j.intimp.2025.114668
  37. Nucleic Acids Res. 2025 Apr 10. pii: gkaf258. [Epub ahead of print]53(7):
    Autophagy induction enhances homologous recombination-associated CRISPR-Cas9 gene editing.
    Hye Jin Nam, Jun Hee Han, Jihyeon Yu, Chang Sik Cho, Dongha Kim, Young Eun Kim, Min Ji Kim, Jeong Hun Kim, Dong Hyun Jo, Sangsu Bae.
      CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated protein 9)-based gene editing via homologous recombination (HR) enables precise gene correction and insertion. However, its low efficiency poses a challenge due to the predominance of nonhomologous end-joining during DNA repair processes. Although numerous efforts have been made to boost HR efficiency, there remains a critical need to devise a novel method that can be universally applied across cell types and in vivo animals, which could ultimately facilitate therapeutic treatments. This study demonstrated that autophagy induction using different protocols, including nutrient deprivation or chemical treatment, significantly improved HR-associated gene editing at diverse genomic loci in mammalian cells. Notably, interacting cofactor proteins that bind to Cas9 under the autophagic condition have been identified, and autophagy induction could also enhance in vivo HR-associated gene editing in mice. These findings pave the way for effective gene correction or insertion for in vivo therapeutic treatments.
    DOI:  https://doi.org/10.1093/nar/gkaf258
  38. Trends Pharmacol Sci. 2025 Apr 14. pii: S0165-6147(25)00066-5. [Epub ahead of print]
    KRASG12C/mTORC1 inhibition: a powerful duo in NSCLC therapeutics.
    Antonios N Gargalionis, Kostas A Papavassiliou, Athanasios G Papavassiliou.
      In a recent report in Nature Communications, Kitai et al. designed a combinational treatment based on targeting the active-state KRASG12C-mutant variant that characterizes a substantial subset of non-small-cell lung cancer (NSCLC) cases. The authors highlighted that dual targeting with KRASG12C (ON) and mammalian target of rapamycin (mTOR) complex (mTORC)-1-selective inhibition potentially provides a new strategy to overcome drug resistance.
    Keywords:  ERK; KRAS(G12C); mTORC1; non-small-cell lung cancer
    DOI:  https://doi.org/10.1016/j.tips.2025.03.009
  39. Autophagy. 2025 Apr 13.
    Dual roles of CXCR4 (C-X-C motif chemokine receptor 4) in promoting entry of ebolavirus and targeting excessive glycoprotein for reticulophagic degradation to facilitate viral fitness.
    Hongxin Huang, Wendi Shi, Huijun Yan, Linjin Fan, Jiajun Lu, Zhenyu Long, Xiaowei Li, Jiao Li, Jie Wang, Linna Liu, Jun Qian.
      Ebola virus disease (EVD) caused by Zaire Ebolavirus (EBOV) infection is a major threat to public health in Africa and even worldwide, due to its extremely high mortality rate. However, there are still no effective antiviral therapies that can completely cure EVD. A comprehensive understanding of virus-host interactions would be beneficial for developing new antiviral agents. Here, we showed that CXCR4-induced macroautophagy/autophagy and was internalized to endosomes by interacting with glycoprotein (GP) on viral particles during EBOV infection; this promoted the EBOV attachment and entry, which was reduced by CXCR4 antagonist and neutralizing antibody. We also found that CXCR4 increased EBOV replication by downregulating cytotoxic GP to promote viral fitness instead of influencing the assembly of viral factory. Mechanistically, excessive EBOV GP could hijack CXCR4 sorting and transporting pathways by their interactions with HGS, one of the key components of the ESCRT machinery; subsequently GP could be carried back to the endoplasmic reticulum by CXCR4, where the E3 ubiquitin ligase RNF185 was recruited to polyubiquitinate GP in a K27- and K63-linked manner. Finally, polyubiquitinated GP was degraded in lysosomes via reticulophagy by interacting with RETREG1 (reticulophagy regulator 1), in an ATG3- and ATG5-dependent manner. Our findings revealed dual roles of CXCR4 in regulation of EBOV life cycle, either acting as an entry factor by interacting with GP on viral particles to facilitate viral entry or targeting excessive GP for reticulophagic degradation, providing new evidence that EBOV hijacked the host vesicular transportation system through efficient virus-host interactions to facilitate viral fitness.
    Keywords:  Autophagy; ER-phagy; EVD; HGS; RETREG1; RNF185
    DOI:  https://doi.org/10.1080/15548627.2025.2492877
  40. MicroPubl Biol. 2025 ;2025
    Autophagy-deficient budding yeast cells are sensitive to freeze-thaw stress.
    Maria James, Grace K Klain, Stacey O Brito, Lupita Trejo, Teresa M A Okello, Verónica A Segarra.
      Autophagy enables eukaryotes to recycle damaged and unneeded materials to ensure survival in times of stress such as starvation. However, the full range of cellular stress responses that activate and require autophagy remains unknown. This study has compared the survival of wild type, atg1Δ, and atg5Δ budding yeast cells following freeze-thaw stress. The results indicate that cells deficient in autophagy exhibit enhanced sensitivity to freeze-thaw stress.
    DOI:  https://doi.org/10.17912/micropub.biology.000929
  41. Geroscience. 2025 Apr 12.
    Bryostatin-1 improves function in arteries with suppressed endothelial cell autophagy.
    Jae Min Cho, Seul-Ki Park, Sohom Mookherjee, Emily Carolyn Peters, Paulo W Pires, J David Symons.
      We have previously reported that when autophagy is suppressed in endothelial cells (ECs), a glycolytic defect limits shear-stress -induced ATP production to an extent that purinergic 2Y1 receptor (P2Y1R)-mediated activation of EC nitric oxide (NO) synthase (eNOS) is compromised. Subsequently we demonstrated the functional relevance of this finding in arteries from mice with genetic, pharmacological, and age-associated EC autophagy impairment. Using gain and loss of function approaches in vitro, we further revealed that p-PKCδT505 serves as a signaling link between P2Y1R activation and NO generation. Here we sought to discern the functional relevance of this observation. First, shear-stress- induced activating phosphorylation of eNOS (p-eNOSS1177) that is otherwise prevented by knockdown of autophagy-related gene 3 (Atg3) in ECs was restored by the PKC agonist bryostatin-1. Next, in murine models of genetic and age-associated EC autophagy compromise, depressed vasodilation displayed by femoral and cerebral arteries was reversed by bryostatin-1 in a manner that could be prevented by concurrent NO synthase inhibition. Finally, the bryostatin-1-mediated normalization of intraluminal flow-induced vasodilation observed in femoral arteries from both models of EC autophagy disruption was mitigated by inhibiting downstream targets of p-PKCδT505 i.e., p-PKDS744/S748 and p-PKDS916. These findings provide evidence that stimulating PKC/PKD has strategic potential to restore compromised endothelial function in pathologies associated with suppressed EC autophagy e.g., aging.
    Keywords:  Aging; Bryostatin-1; Endothelial cell; Nitric oxide
    DOI:  https://doi.org/10.1007/s11357-025-01650-5
  42. bioRxiv. 2025 Apr 10. pii: 2025.04.03.647084. [Epub ahead of print]
    STAR/STARD1: a mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
    Prasanthi P Koganti, Amy H Zhao, Michael C Kern, Auriole C R Fassinou, Vimal Selvaraj.
      The import of cholesterol to the inner mitochondrial membrane by the steroidogenic acute regulatory protein (STAR/STARD1) is essential for de novo steroid hormone biosynthesis and the acidic pathway of bile acid synthesis. This robust system, evolved to start and stop colossal cholesterol movement, ensures pulsatile yet swift mitochondrial steroid metabolism in cells. Nonetheless, the proposed mechanism and components involved in this process has remained a topic of ongoing debate. In this study, we elucidate the mitochondrial import machinery and structural aspects of STAR, revealing its role as an intermembrane space cholesterol shuttle that subsequently undergoes rapid degradation by mitophagy. This newfound mechanism illuminates a fundamental process in cell biology and provides precise interpretations for the full range of human STAR mutation-driven lipoid congenital adrenal hyperplasia in patients.
    DOI:  https://doi.org/10.1101/2025.04.03.647084
  43. Adv Sci (Weinh). 2025 Apr 15. e2414830
    Inhibiting the Histone Demethylase Kdm4a Restrains Cardiac Fibrosis After Myocardial Infarction by Promoting Autophagy in Premature Senescent Fibroblasts.
    Ming Jin, Chuling Li, Zhaoyi Wu, Zhenquan Tang, Jingfang Xie, Guoquan Wei, Zhiwen Yang, Senlin Huang, Yijin Chen, Xinzhong Li, Yanmei Chen, Wangjun Liao, Yulin Liao, Guojun Chen, Hao Zheng, Jianping Bin.
      Premature senescent fibroblasts (PSFs) play an important role in regulating the fibrotic process after myocardial infarction (MI), but their effect on cardiac fibrosis remains unknown. Here, the investigation is aimed to determine whether PSFs contribute to cardiac fibrosis and the underlying mechanisms involved. It is observed that premature senescence of fibroblasts is strongly activated in the injured myocardium at 7 days after MI and identified that Kdm4a is located in PSFs by the analysis of scRNA-seq data and immunostaining staining. Moreover, fibroblast specific gain- and loss-of-function assays showed that Kdm4a promoted the premature senescence of fibroblasts and cardiac interstitial fibrosis, contributing to cardiac remodeling in the advanced stage after MI, without influencing early cardiac rupture. ChIP-seq and ChIP-PCR revealed that Kdm4a deficiency promoted autophagy in PSFs by reducing Trim44 expression through increased levels of the H3K9me3 modification in the Trim44 promoter region. Furthermore, a coculture system revealed that Kdm4a overexpression increased the accumulation of PSFs and the secretion of senescence-associated secretory phenotype (SASP) factors, subsequently inducing cardiac fibrosis, which could be reversed by Trim44 interference. Kdm4a induces the premature senescence of fibroblasts through Trim44-mediated autophagy and then facilitates interstitial fibrosis after MI, ultimately resulting in cardiac remodeling, but not affecting ventricular rupture.
    Keywords:  Kdm4a; cardiac fibrosis; premature senescent fibroblasts
    DOI:  https://doi.org/10.1002/advs.202414830
  44. Geroscience. 2025 Apr 15.
    German longevity study reveals novel rare pro-longevity alleles clustering in mTOR signaling pathway.
    Regeneron Genetics Center
      In this study, we investigated the contribution of rare coding variants to human longevity by analyzing whole exome sequencing data from 1245 German long-lived individuals (LLI) and 4105 geographically matched younger controls. We identified novel exome-wide significant associations at both the single-variant and gene level, with a significant over-representation of genes involved in mechanistic target of rapamycin (mTOR) signaling. As such, three rare single variants in the mTOR-pathway genes RPS6, FLCN, and SIK3 were enriched in LLI. Additionally, RWDD1 emerged as a strong candidate gene for longevity, with LLI exhibiting a statistically significant burden of rare missense variants in this gene. Other associations involved PRAC2, SLC16 A6, FOCAD, IHH, MESD, HOXA4, and DNAJB13. Furthermore, we observed an enrichment of protein-truncating variants in the genes ASXL1 and TET2 amongst LLI, likely as a result of clonal haematopoiesis. The study emphasizes the role of rare variants in human longevity, particularly through mTOR signaling.
    Keywords:  Exome-wide association analysis; Genetics; Human longevity; MTOR signaling; Rare variants
    DOI:  https://doi.org/10.1007/s11357-025-01640-7
  45. J Neural Transm (Vienna). 2025 Apr 17.
    Sphingolipidoses: expanding the spectrum of α-synucleinopathies.
    Daniel Erskine, Agnieszka K Bronowska, Tiago F Outeiro, Johannes Attems.
      Although α-synuclein pathology is typically associated with Lewy body diseases and multiple systems atrophy, increasing evidence indicates that it also occurs in a group of lysosomal storage disorders termed sphingolipidoses caused by the incomplete degradation, and subsequent accumulation, of a class of lipids termed sphingolipids. Notably, a number of genes that cause sphingolipidoses are also risk genes for Lewy body diseases, suggesting aetiological links between these distinct disorders. In the present review, we discuss the sphingolipidoses in which α-synuclein pathology has been reported: Gaucher disease, Krabbe disease, metachromatic leukodystrophy, Tay-Sachs disease and Anderson-Fabry disease, and describe the characteristic clinical and pathological features of these disorders, in addition to the evidence suggesting α-synuclein pathology occurs in these disorders. Finally, we evaluate the pathological mechanisms that underlie these rare disorders, with particular attention to how the enzymatic deficiency, substrate accumulation, or both, could contribute to the genesis of α-synuclein pathology and the implications of this for Lewy body diseases.
    Keywords:  Alpha-synuclein; Lewy; Lysosomal storage disorder; Neurodegeneration; Parkinson’s; Sphingolipid
    DOI:  https://doi.org/10.1007/s00702-025-02925-z
  46. Sci Rep. 2025 Apr 18. 15(1): 13401
    Multi-omics analysis of two rat models reveals potential role of vesicle transport and autophagy in right ventricular remodeling.
    Yuhan Qin, Jing Zhang, Aiwei Wang, Wei Sun, Xiaohan Qin, Feng Qi, Yufei Wang, Le Du, Xiaoyan Liu, Haidan Sun, Zhengguang Guo, Xiaoxiao Guo.
      Right ventricular failure as a severe consequence of pulmonary arterial hypertension (PAH) is an independent risk factor for poor prognosis, although the pathogenesis of right ventricular remodeling (RVR) remains unclear. Exploring the shared molecular pathways and key molecules in the right ventricle in monocrotaline (MCT) and pulmonary artery banding (PAB) rat models may reveal critical RVR mechanisms. Untargeted proteome and metabolome analysis were performed on the right ventricular myocardium of two RVR models (MCT-induced PAH rats and PAB-operated rats) to identify the altered proteins and metabolites, followed by validation using parallel reaction monitoring analysis and quantitative real-time polymerase chain reaction (qPCR). The multi-omics profiles of MCT and PAB rat models were compared to explore the key dysregulated molecules and pathways in RVR. Our proteomics study identified 25 shared RVR-altered differentially expressed proteins. Multiple common biological pathways were identified between PAB and MCT rat models, encompassing myocardial remodeling and energy metabolism alternation, etc. Various molecules and pathways related to vesicle transport and autophagy were identified, including nidogen-1, the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) signaling pathway, and the microautophagy pathway (all previously unreported in RVR). Glycerophospholipid metabolism was the sole statistically significant common metabolic pathway enriched by metabolomics. Underreported biological processes, including vesicle transport and autophagy, may contribute to the pathophysiology of PAH-induced RVR.
    Keywords:  Autophagy; Metabolome; Proteome; Right ventricular remodeling; Vesicle transport
    DOI:  https://doi.org/10.1038/s41598-025-98347-8
  47. Nat Metab. 2025 Apr 14.
    Protein-responsive gut hormone tachykinin directs food choice and impacts lifespan.
    Nadja Ahrentløv, Olga Kubrak, Mette Lassen, Alina Malita, Takashi Koyama, Amalie S Frederiksen, Casper M Sigvardsen, Alphy John, Pernille E H Madsen, Kenneth V Halberg, Stanislav Nagy, Cordelia Imig, Erik A Richter, Michael J Texada, Kim Rewitz.
      Animals select food based on hungers that reflect dynamic macronutrient needs, but the hormonal mechanisms underlying nutrient-specific appetite regulation remain poorly defined. Here, we identify tachykinin (Tk) as a protein-responsive gut hormone in Drosophila and female mice, regulated by conserved environmental and nutrient-sensing mechanisms. Protein intake activates Tk-expressing enteroendocrine cells (EECs), driving the release of gut Tk through mechanisms involving target of rapamycin (TOR) and transient receptor potential A1 (TrpA1). In flies, we delineate a pathway by which gut Tk controls selective appetite and sleep after protein ingestion, mediated by glucagon-like adipokinetic hormone (AKH) signalling to neurons and adipose tissue. This mechanism suppresses protein appetite, promotes sugar hunger and modulates wakefulness to align behaviour with nutritional needs. Inhibiting protein-responsive gut Tk prolongs lifespan through AKH, revealing a role for nutrient-dependent gut hormone signalling in longevity. Our results provide a framework for understanding EEC-derived nutrient-specific satiety signals and the role of gut hormones in regulating food choice, sleep and lifespan.
    DOI:  https://doi.org/10.1038/s42255-025-01267-0
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