bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2026–03–22
27 papers selected by
Viktor Korolchuk, Newcastle University
  1. Control of lysosome function by the GTPase-activating protein TBC1D9B and its binding partner TMEM55B.
  2. Lysosomal phosphoinositide turnover acts upstream of RagGTPase-mTORC1 and controls muscle growth.
  3. Targeting the mTOR Pathway with Natural Products: A Potential Therapeutic Approach for Autism Spectrum Disorders.
  4. ZDHHC9 palmitoylates LAMTOR1 to promote renal cell carcinoma malignant progression.
  5. ATG2A connects lipid droplets and the ER to regulate lipid storage.
  6. ATG8 and protein ATG8ylation - more than just Another TaG?
  7. The redundant protein synthesis gene Aimp1 challenges the canonical inverse relationship between translation and autophagy.
  8. Focusing on the Apolipoprotein M-Mitophagy Axis: A Mechanism for Renal Protection in Diabetic Nephropathy.
  9. Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair.
  10. O-GlcNAcylation of YAP1 promotes lung transplant ischemia-reperfusion injury via binding to HIF1α transcription factor and activating autophagy and mitophagy.
  11. SEL1L-HRD1 ERAD-autophagy interplay maintains mitochondrial homeostasis in brown adipocytes.
  12. Ubiquitin signatures on aggregating proteins in neurodegeneration.
  13. Do metabolic fluxes change with age?
  14. Mitochondria acidify lysosomes through membrane contacts.
  15. Androgen receptor-dependent DRAM1 activation drives autophagic resistance to BRAF inhibitors in BRAFV600-mutant melanoma.
  16. Targeting ULK1 and USP20 to modulate autophagy and chemosensitivity in cancer cell lines.
  17. Autophagy is essential for survival and function of polyploid giant cancer cells under therapeutic stress.
  18. The dual impact of GBA1 in disease: from germline mutations in neurological disorders to alterations in cancer.
  19. Cholesterol transporter GRAMD1B in tauopathies: A regulator of lipid homeostasis and tau pathology via autophagy flux.
  20. Astrocytic autophagy: From resilience to vulnerability in aging and neurodegeneration.
  21. Oxidative phosphorylation and mitochondrial dynamics are regulated by Sestrin2 to maintain cellular function.
  22. Lysosomal down-regulation of the mu opioid receptor is opposed by the Retromer complex.
  23. Neuroprotective effects of DPP-4 inhibitors sitagliptin and vildagliptin in Parkinson's disease via autophagy modulation.
  24. PGC-1α exacerbates apoptosis to induce HIF-1α/BNIP3 mediated mitophagy in heart failure.
  25. Rapamycin treatment reduces CD11c+ microglia and increases amyloid plaque load in 5xFAD mice.
  26. The α-synuclein proteostasis network and its translational applications in Parkinson's disease.
  27. Bip1 regulates AMPK signaling in response to endoplasmic reticulum stress.
  1. Nat Commun. 2026 03 14. pii: 2487. [Epub ahead of print]17(1):
    Control of lysosome function by the GTPase-activating protein TBC1D9B and its binding partner TMEM55B.
    Valentin Duhay, Miaomiao Tian, Klaudia Kosieradzka, Michael Ebner, Wen-Ting Lo, Michael Krauss, Henner-Linus Sprengel, Matthias Voss, Mara Riechmann, Jeffrey N Savas, Michael Schwake, Volker Haucke, Markus Damme.
      Lysosomes are highly dynamic organelles that serve antagonistic functions as terminal catabolic stations for the degradation of macromolecules and as central metabolic decision centers for anabolic growth signaling. Lysosome dysfunction is implicated in various human diseases. The physiological roles of lysosomes are linked to the control of lysosome position and dynamics via the activity of the kinesin-activating small GTPase ARL8. How the activity of ARL8 is regulated remains poorly understood. Here, we identify the GTPase-activating Tre-2/Bub2/Cdc16 (TBC) domain protein TBC1D9B as a critical negative regulator of ARL8B function. We demonstrate that TBC1D9B is associated with the lysosomal membrane protein TMEM55B, directly binds to ARL8B-GTP, and stimulates its GTPase activity. Knockout of TBC1D9B or its binding partner TMEM55B causes lysosome dispersion, defective autophagic flux, and impairs the adaptive degradative response of cells to limiting nutrient supply. These lysosomal phenotypes of TBC1D9B loss are occluded by concomitant depletion of ARL8 in cells. Collectively, our data unravel a key role for TBC1D9B in controlling lysosome function by serving as a negative regulator of ARL8 activity.
    DOI:  https://doi.org/10.1038/s41467-026-70345-y
  2. Nat Metab. 2026 Mar 18.
    Lysosomal phosphoinositide turnover acts upstream of RagGTPase-mTORC1 and controls muscle growth.
    Melanie Picot, Nesrine Hifdi, Mathilde Vaucourt, Melanie Mansat, Peng Li, Isabel Singer, Gaëtan Chicanne, Alexandre Stella, Shen Kuang, Caterina Miceli, Nathaniel F Henneman, Bernard Payrastre, Marie Vandromme, Odile Schiltz, Ivan Nemazanyy, Mariana E G de Araujo, Ganna Panasyuk, Julien Viaud, Michael Lämmerhofer, Karim Hnia.
      Lysosomes act as metabolic signalling hubs that integrate nutrient availability to coordinate anabolic and catabolic programmes. Mechanistic target of rapamycin complex 1 (mTORC1) is activated at the lysosomal surface by amino acids through RagGTPases recruited by the lysosomal adaptor and MAPK and mTOR activator complex, yet the contribution of lysosomal lipid composition to this pathway remains unclear. Here we identify lysosomal phosphoinositides, PI3P and PI(3,5)P2, as key regulators of lysosomal adaptor and MAPK and mTOR activator complex stability and dynamics at the lysosome. These lipid pools are controlled by the phosphoinositide 3-phosphatase MTM1, mutated in myotubular myopathy, via endoplasmic reticulum-lysosome membrane contact sites. Under endoplasmic reticulum stress, MTM1-dependent phosphoinositide remodelling suppresses RagGTPase-mTORC1 signalling, thereby regulating anabolic-catabolic balance during myogenic differentiation. Restoring mTORC1 activity or lysosomal phosphoinositide homeostasis rescues Rag-dependent signalling and muscle growth in cellular and mouse models of myopathy, uncovering a lysosome-centred metabolic checkpoint with direct disease relevance.
    DOI:  https://doi.org/10.1038/s42255-026-01484-1
  3. Curr Neuropharmacol. 2026 Mar 10.
    Targeting the mTOR Pathway with Natural Products: A Potential Therapeutic Approach for Autism Spectrum Disorders.
    Tayebeh Noori, Seyede Zahra Hosseini, Seyede Darya Alavi, Antoni Sureda, Samira Shirooie.
      Autism spectrum disorders (ASD) are complex neurodevelopmental conditions characterized by a diverse range of challenges and strengths in social communication, behavior, and sensory processing, with wide variation in presentation and severity among individuals. Treatment for ASD symptoms typically includes stimulants, modafinil, atomoxetine, antidepressants, antipsychotics, and natural products. The mechanistic target of rapamycin (mTOR), a serine/threonine kinase, is dysregulated in many human diseases, leading to abnormal synapse formation, neuroinflammation, and mitochondrial dysfunction. Natural products, due to their wide range of bioactive compounds and relatively low toxicity, have emerged as promising modulators of this pathway. Several phytochemicals-including curcumin, resveratrol, and epigallocatechin gallate-have demonstrated the ability to modulate mTOR signaling and improve neurobehavioral outcomes in preclinical models of ASD. mTORC1 and mTORC2 are key regulators of cellular processes, with mTORC1 being largely sensitive to nutrient availability and mTORC2 playing a crucial role in cell growth, proliferation, motility, and autophagy, which is modulated by the PI3K/Akt/mTOR pathway. Future research should examine the relationship between autism and the mTOR signaling pathway, as well as the phytochemicals that may contribute to improving the condition through this pathway.
    Keywords:  Autism spectrum disorders; natural products; mTOR; neurodevelopmental disorders.
    DOI:  https://doi.org/10.2174/011570159X388575251126041202
  4. Cell Death Dis. 2026 Mar 19.
    ZDHHC9 palmitoylates LAMTOR1 to promote renal cell carcinoma malignant progression.
    Bo Liu, Tao Hou, Xizhi Liu, Lu Liu, Zhiqiang Ma, Yujiao Zhang.
      The lysosomal regulator complex member LAMTOR1 serves as a crucial pivot that recruits the mechanistic target of rapamycin complex 1 (mTORC1) to the lysosomal surface, thereby influencing biological processes such as cell growth and cancer progression. In renal cell carcinoma (RCC), existing studies reveal that mTORC1 signaling contributes to cancer progression. However, the precise regulatory mechanisms underlying mTOR signaling in RCC remain unclear and warrant further investigation. Here, we demonstrate that the palmitoylation enzyme Zinc Finger DHHC-Type Containing 9 (ZDHHC9) activates the mTOR signaling pathway, thereby accelerating cancer progression and highlighting its potential role in RCC. In our study, we identified that ZDHHC9 specifically palmitoylates LAMTOR1 at its Cys3/4 residues, enhancing the recruitment of mTORC1 and subsequently activating the mTOR signaling cascade. Collectively, our findings provide novel insights into the pathogenesis of RCC and establish ZDHHC9 as a key mediator of RCC progression through the palmitoylation of LAMTOR1, which may serve as a promising target for the diagnosis and treatment of this malignancy.
    DOI:  https://doi.org/10.1038/s41419-026-08558-8
  5. Autophagy. 2026 Mar 18. 1-2
    ATG2A connects lipid droplets and the ER to regulate lipid storage.
    Helin Elhan, Justin L Korfhage, Thomas J Melia, Abdou Rachid Thiam.
      The endoplasmic reticulum (ER) must carefully regulate the levels of nonmembrane lipids such as diacylglycerol (DAG), phosphatidic acid (PA), and triacylglycerol (TAG) to maintain membrane integrity and prevent lipotoxic stress. While ATG2A is well known as a lipid transfer protein essential for autophagosome formation, its role at lipid droplet (LD) contact sites has remained unclear. In our recent work, we show that ATG2A functions beyond its typical role in autophagy as a key regulator of lipid storage, transferring DAG, TAG, and PA from the ER to LDs and recruiting the TAG synthesis enzyme DGAT2 to promote LD expansion. Without ATG2A, lipids accumulate in the ER, leading to smaller, more numerous nucleated LDs rather than proper growth. Notably, ATG2A-mediated DAG transfer recruits DGAT2 to LD surfaces, enabling local TAG synthesis that prevents nonmembrane lipid accumulation in the ER. This cooperative process reveals ATG2A's dual role in both autophagy and lipid storage, highlighting an unexpected link between autophagy machinery and lipid storage.
    Keywords:  ATG2A; DGAT2; ER quality control; diacylglycerol; lipid droplets; lipid transfer
    DOI:  https://doi.org/10.1080/15548627.2026.2645161
  6. Autophagy. 2026 Mar 20. 1-9
    ATG8 and protein ATG8ylation - more than just Another TaG?
    Fabian Gerth, Simone Kosol, Natasha Aley, Alexander Agrotis, Robin Ketteler.
      Since its discovery as a key component of the autophagosome membrane, the small ubiquitin-like protein ATG8 and its mammalian homologs (ATG8s) have garnered a lot of attention. Many researchers use it as a marker for autophagosome number, size and composition. A lot of research has focussed on its function in forming complexes required for autophagosome-lysosome fusion or generally, its interaction with other proteins via the ATG8-family interacting motif/AIM. Many additional functions have been discovered, for instance in non-canonical autophagy processes and in the nucleus. The list of known functions of ATG8 are ever expanding, and, most recently, evidence has emerged that, similar to ubiquitin, ATG8 can modify proteins by covalent attachment to a lysine residue (protein ATG8ylation). In this review, we aim to summarize the current literature on protein ATG8ylation and highlight the currently known substrates. We propose strategies to investigate this modification and provide an outlook for its possible cellular function.Abbreviations: ATG: autophagy related; DUBs: de-ubiquitinating enzymes; GABARAPL: GABA type A receptor associated protein like; GIR: GABARAP-interacting region; LIR: LC3-interacting region; MAP1LC3: microtubule associated protein 1 light chain 3; RMSD: root mean square; UBL: ubiquitin-like; UPS: ubiquitin-proteasome-system.
    Keywords:  ATG4B; ATG8; ATG8ylation; LC3ylation; autophagy; ubiquitin-like
    DOI:  https://doi.org/10.1080/15548627.2026.2642981
  7. Commun Biol. 2026 Mar 20.
    The redundant protein synthesis gene Aimp1 challenges the canonical inverse relationship between translation and autophagy.
    Daniel D Lee, Bailey N Rutkowski, Noah C Wilson, Rafael D Kuc, Carla D Schwarz, Margaret A Schwarz.
      The fundamental processes of protein synthesis and autophagy are encoded by genes that vary in their essentiality for cellular fitness, and these genes are often inversely coupled through mTORC1 signaling. This study leverages analyses of gene essentiality genomic studies, to identify genes that are not only non-essential for cellular fitness, but also redundant for either protein synthesis or autophagy. This genomic approach identifies Aimp1, a highly conserved member of multi-aminoacyl tRNA synthetase complex thought to promote protein synthesis, Aimp1, as a limiter of autophagy in part through uncoupling of mTORC1 activity while minimally affecting protein synthesis. Transcriptomics analyses demonstrate that during immune responses protein synthesis and autophagy are inversely related. Depletion of Aimp1 in murine myeloid cells impairs innate immunity kinetics, thus unmasking an exemption in the inverse relationships between protein synthesis and autophagy. Our findings reveal that the functional redundancy of select protein synthesis genes, such as Aimp1, can reinforce autophagic activity, thereby challenging the canonical inverse relationship between translation and autophagy and highlighting a novel mechanism for maintaining cellular homeostasis.
    DOI:  https://doi.org/10.1038/s42003-026-09892-5
  8. J Diabetes Res. 2026 ;2026(1): e1498605
    Focusing on the Apolipoprotein M-Mitophagy Axis: A Mechanism for Renal Protection in Diabetic Nephropathy.
    Tianlei Chen, Min Yang.
      Diabetic nephropathy (DN), a predominant cause of end-stage renal disease (ESRD), is primarily driven bfigolic disturbances and mitochondrial dysfunction. Apolipoprotein M (ApoM), a protein associated with high-density lipoprotein (HDL), is notably downregulated in DN and is correlated with a decline in renal function. Recent studies have identified a protective bidirectional axis between ApoM and mitophagy, the selective autophagy of mitochondria. ApoM, chiefly through its role as a carrier for sphingosine-1-phosphate (S1P), enhances mitophagy by activating the silent information regulator 1 (SIRT1) and parkin induced kinase 1 (PINK1)/Parkin pathways, thereby improving mitochondrial quality control. Conversely, mitophagy facilitates ApoM synthesis by supplying sufficient adenosine triphosphate (ATP) for its production and the assembly of HDL. In the context of DN, hyperglycemia disrupts this reciprocal relationship, leading to a detrimental cycle of impaired mitophagy and reduced ApoM, which exacerbates renal injury. Targeting the ApoM-mitophagy axis through ApoM enhancement or mitophagy activation emerges as a promising therapeutic approach for personalized renal protection in DN. This review synthesizes the mechanistic interplay between lipid metabolism and mitochondrial quality control, emphasizing its translational potential and the necessity for further investigation.
    Keywords:  apolipoprotein m; diabetic nephropathy; lipid metabolism; mitophagy; sphingosine-1-phosphate
    DOI:  https://doi.org/10.1155/jdr/1498605
  9. EMBO J. 2026 Mar 20.
    Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair.
    Di Chen, Antony Fearns, Christopher J Peddie, Maximiliano G Gutierrez.
      Endomembrane damage of intracellular vesicles triggers signals that activate membrane repair in mammalian cells to restore homeostasis. However, the signals that drive diverse membrane repair recruitment at the individual organelle level are unknown. Here by recording Ca2+ leakage history with a newly developed Ca2+ probe in human macrophages, we discovered that Ca²⁺ leakage serves as a conserved signal that triggers ATG8/LC3 lipidation after different types of sterile membrane damage. The damaged compartments consisted of both single membrane and multilayered membrane structures undergoing extensive membrane remodelling. We show the complexity and acidification of these ATG8/LC3-positive compartments depends on the nature of the membrane damage trigger. Functionally, the formation of these multimembrane ATG8/LC3-positive compartments restricted membrane damage independently of canonical autophagy and the recruitment of ESCRT components CHMP2A/CHMP4B. Altogether, we show that endolysosomal Ca²⁺ leakage triggers non-canonical LC3 lipidation on damaged membranes to promote membrane repair in human macrophages.
    Keywords:  Ca2+ Leakage; Lysosome Damage; Macrophages; Membrane Repair; Non‑canonical LC3 Lipidation
    DOI:  https://doi.org/10.1038/s44318-026-00741-z
  10. Cell Death Dis. 2026 Mar 15.
    O-GlcNAcylation of YAP1 promotes lung transplant ischemia-reperfusion injury via binding to HIF1α transcription factor and activating autophagy and mitophagy.
    Shaohua Dai, Xuemei Wan, Lingchun Xia, Lei Xu, Chunfan Xie, Guohui Wang, Jian Tang.
      Lung transplant ischemia-reperfusion injury poses a significant challenge in transplantation medicine, often causing severe complications and poor patient outcomes. Our study focused on the role of O-GlcNAcylation of Yes-associated protein 1 (YAP1) in exacerbating this injury by regulating autophagy and mitochondrial autophagy pathways. We found that hypoxia-reoxygenation robustly activated the Hippo-YAP1 signaling pathway, leading to increased damage in lung epithelial cells. Concurrently, autophagy and mitochondrial autophagy levels were significantly upregulated, indicating cellular stress responses. During actual lung transplantation, ischemia-reperfusion resulted in a marked increase in autophagy and mitochondrial autophagy levels, accompanied by elevated tissue damage. Notably, YAP1 played a crucial role in orchestrating these processes, as its knockdown reduced autophagy and mitochondrial autophagy levels under both hypoxia-reoxygenation and ischemia-reperfusion conditions. We further elucidated that OGT-mediated O-GlcNAc modification of YAP1 enhanced its interaction with HIF1α, activating downstream hypoxia-responsive molecules. Knockdown of the key enzyme OGT significantly mitigated autophagy, mitophagy, and associated damage in lung epithelial cells and transplant tissues subjected to hypoxia-reoxygenation and ischemia-reperfusion. These findings reveal the intricate interplay between O-GlcNAcylation of YAP1, HIF1α binding, autophagy activation, and mitochondrial autophagy in driving lung transplant ischemia-reperfusion injury, suggesting potential therapeutic targets for ameliorating its detrimental effects.
    DOI:  https://doi.org/10.1038/s41419-026-08548-w
  11. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2529914123
    SEL1L-HRD1 ERAD-autophagy interplay maintains mitochondrial homeostasis in brown adipocytes.
    Xinxin Chen, Siwen Wang, Mauricio Torres, Sijie Hao, Shengyi Sun, Ling Qi.
      Mitochondrial integrity is central to energy homeostasis, particularly in brown adipose tissue where dynamic remodeling fuels thermogenesis. Two major proteostatic systems, the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD) pathway and autophagy, have been shown to intersect in vitro, but their physiological coordination in metabolically active tissues remains unclear. Here, we demonstrate that ERAD and autophagy act in synergy to safeguard mitochondrial integrity in brown adipocytes. Using various adipocyte-specific knockout (KO) mouse models and high-resolution ultrastructural 2D and 3D imaging, we show that simultaneous deletion of Sel1L and Atg7 (double KO, DKO) causes striking mitochondrial abnormalities under room temperature, absent in single KO or Sel1L-Ire1a double knockout mice. DKO adipocytes accumulate hyperfused megamitochondria extensively penetrated by ER tubules, accompanied by ER expansion, excessive ER-mitochondrial contacts, and impaired thermogenesis. These findings reveal that SEL1L-HRD1 ERAD and autophagy cooperate, rather than act redundantly, to maintain mitochondrial integrity in brown fat, uncovering a previously unrecognized mitochondrial surveillance mechanism based on ERAD-autophagy crosstalk.
    Keywords:  3D FIB-SEM; ER–mitochondrial contacts; brown adipocytes; megamitochondria; thermogenesis
    DOI:  https://doi.org/10.1073/pnas.2529914123
  12. Essays Biochem. 2025 Dec 22. pii: EBC20253046. [Epub ahead of print]69(5):
    Ubiquitin signatures on aggregating proteins in neurodegeneration.
    Subhashree Sahoo, Amrita Arpita Padhy, Kummari Shivani, Ashish Misra, Parul Mishra.
      The aberrant accumulation of misfolded proteins marked by cellular dysfunction and progressive neuronal loss is the hallmark of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. This review examines the pivotal role of ubiquitin modifications in altering the fate of aggregation-prone proteins such as tau, α-synuclein, mutant huntingtin, TAR DNA-binding protein 43 and superoxide dismutase 1. The ubiquitin signatures identified by their linkage types, chain architectures and site specificities emerge as a complex regulatory language that influences the clearance, aggregation or cellular propagation of these aggregating proteins. The dysregulation of other components of the ubiquitin association pathways, such as impaired E3 ligases and deubiquitinases, also contributes to the inefficient protein disposal and disease progression. Understanding how ubiquitin signatures alter the spatiotemporal dynamics of aggregating proteins is critical for advancing our knowledge of disease biology. Here, we focus on the role of ubiquitin modifications and their associated regulators affecting protein fate and neurotoxicity, and highlight the current therapeutic strategies targeting the degradation of aggregating proteins to uncover potential avenues for treating neurodegenerative diseases.
    Keywords:  autophagy; neurodegenerative disease; proteasome; ubiquitin; ubiquitin E3 ligases
    DOI:  https://doi.org/10.1042/EBC20253046
  13. Trends Endocrinol Metab. 2026 Mar 17. pii: S1043-2760(26)00013-5. [Epub ahead of print]
    Do metabolic fluxes change with age?
    Sebastian J Hofer, Anna Katharina Simon, Frank Madeo.
      Metabolomes change with age. Yet, fluxomics points to a contradiction: Jankowski et al. in Cell Metabolism report shifts in metabolite concentrations in aged mice, alongside largely preserved metabolite fluxes, evoking important questions on the nature of age-related metabolic disturbances. We discuss how this might recalibrate our understanding of aging metabolism.
    Keywords:  age-associated diseases; aging; autophagy; geroscience; metabolism
    DOI:  https://doi.org/10.1016/j.tem.2026.01.013
  14. Cell Rep. 2026 Mar 15. pii: S2211-1247(26)00190-7. [Epub ahead of print]45(3): 117112
    Mitochondria acidify lysosomes through membrane contacts.
    Zhiqi Tian, Rui Chen, Guiqian Fang, Kangqiang Qiu, Weijun Wu, Xintian Shao, Daili Liu, Huilin Que, Xueqian Wang, Ji Gao, Jianyu Zhang, Bidyut Kundu, Qixin Chen, Jun-Lin Guan, Yueguang Rong, Ben Zhong Tang, Kai Li, Yujie Sun, Jiajie Diao.
      The acidic environment within the lysosome lumen is essential for its digestive function. However, the source of protons responsible for acidification has remained elusive. Here, using a molecular probe to monitor lysosomal digestion, we discovered enhanced lysosome content degradation at mitochondria-lysosome contact (MLC) sites, which was caused by lysosomal acidification. Using a mitochondrial probe, we observed a proton flux from mitochondria to lysosomes at these MLC sites. Furthermore, we found that physically bringing mitochondria and lysosomes into close proximity can increase lysosome acidification to enhance content digestion under disease conditions. These findings unveil a crucial physiological role of MLCs in cellular functions.
    Keywords:  CP: cell biology; lysosome acidification; mitochondria-lysosome contact; proton flux
    DOI:  https://doi.org/10.1016/j.celrep.2026.117112
  15. Cell Death Dis. 2026 Mar 16. pii: 265. [Epub ahead of print]17(1):
    Androgen receptor-dependent DRAM1 activation drives autophagic resistance to BRAF inhibitors in BRAFV600-mutant melanoma.
    Ding Zhi, Baojin Wu, Junyi Yang, Daohe Wang, Jing Qiao, Fanli Guo.
      BRAFV600-mutant melanoma relies on hyperactivation of the MAPK/ERK pathway for tumorigenesis, with BRAF/MEK inhibitors (BRAFi/MEKi) improving patient outcomes. However, therapeutic resistance frequently emerges, and male patients show poorer responses and outcomes, partially linked to androgen receptor (AR) overexpression. Here, we uncover a mechanistic link between AR signaling and autophagic resistance in BRAFV600-mutant melanoma. We show that BRAFi treatment upregulates AR expression, which induces cytoprotective autophagy through transcriptional activation of DRAM1, a key autophagy-related gene. Functional studies reveal that AR-driven autophagy confers resistance to BRAFi by enhancing cellular survival under therapeutic stress. Our findings establish AR-regulated autophagy as a critical resistance mechanism and provide preclinical evidence for combining AR-targeting PROTAC degrader ARV110 with autophagy inhibitors to overcome BRAFi resistance.
    DOI:  https://doi.org/10.1038/s41419-026-08547-x
  16. Biomed Rep. 2026 Apr;24(4): 51
    Targeting ULK1 and USP20 to modulate autophagy and chemosensitivity in cancer cell lines.
    Tuqa Abu Thiab, Malek Zihlif, Dana Alqudah, Amer Imraish.
      Autophagy is a conserved catabolic process essential for maintaining cellular homeostasis by degrading and recycling damaged organelles and misfolded proteins. In cancer, autophagy plays a dual role, acting as both a tumor suppressor and promoter depending on the stage and context. Unc-51-like kinase 1 (ULK1), a key initiator of autophagy, is tightly regulated by USP20, a de-ubiquitinase that stabilizes ULK1 by preventing its lysosomal degradation. However, their roles in cancer progression and treatment response remain poorly understood. The present study investigated the baseline expression of ULK1 and USP20 across several cancer cell lines and evaluates the effects of their silencing on chemosensitivity. The findings of the present study showed that ULK1 was highly expressed in MCF-7 breast cancer cells and minimally in U87 glioblastoma cells. USP20 showed high expression in MCF-7, MDA-MB-231 and HepG2, and low expression in others. Combined silencing of ULK1 and USP20 with chemotherapy altered drug sensitivity across cancer types. ULK1 knockdown increased drug sensitivity and induced cell death in HepG2, MDA-MB-231 and PanC1 cell lines, but conferred chemoresistance in MCF-7, A549 and U87 cancer cells. Similarly, USP20 silencing sensitized MCF-7, HepG2 and PanC1 cells to chemotherapy, while enhancing survival in U87 cells. These results suggest that ULK1 and USP20 have cancer-type-specific roles in modulating autophagy and chemotherapy response. Targeting these proteins may provide novel therapeutic strategies to overcome chemoresistance and promote apoptosis in cancer treatment.
    Keywords:  USP20; Unc-51-like kinase 1; apoptosis; autophagy; cancer; chemosensitivity
    DOI:  https://doi.org/10.3892/br.2026.2124
  17. Cancer Lett. 2026 Mar 14. pii: S0304-3835(26)00194-1. [Epub ahead of print] 218431
    Autophagy is essential for survival and function of polyploid giant cancer cells under therapeutic stress.
    D Ghosh, B White, X Lu, M Perricone, M Zhou, B Xuan, Y Li, Y Wang, M R Dawson.
      Polyploid giant cancer cells (PGCCs) are enlarged, multinucleated tumor cells that arise in response to stressors such as chemotherapy and are increasingly recognized as key drivers of recurrence and metastasis in aggressive cancers. Found in triple-negative breast cancer (TNBC) and ovarian cancer (OC), PGCCs can survive cytotoxic therapy in a dormant state and later produce chemoresistant progeny through amitotic budding. Here, we investigated the role of autophagy in paclitaxel (PTX)-induced PGCC survival, nuclear maintenance, and migration. PGCCs generated from MDA-MB-231 and HEY cells were significantly larger, more heterogeneous, and more resistant to PTX than parent cells. Transcriptomic profiling revealed enrichment of metabolic and cytoskeletal pathways, with strong upregulation of autophagy-related genes, including SQSTM1 (P62), LC3, and LAMP1. PGCCs exhibited elevated oxidative stress and marked induction of mitochondrial superoxide dismutase 2 (SOD2). p62 was localized near micronuclei, and prolonged autophagy inhibition with Bafilomycin A1 reduced nuclear size, heterogeneity, and micronuclei number. PGCCs also displayed a dispersed vimentin intermediate filament network that scaffolded autophagic structures; autophagy inhibition impaired migration in PGCC-derived daughter cells. These findings identify autophagy as a critical process sustaining PGCC survival, structural integrity, and motility, and suggest that targeting autophagy may disrupt PGCC-driven recurrence in aggressive cancers.
    Keywords:  Autophagy; Daughter cells; Micronuclei; PGCC; Paclitaxel; Vimentin; p62
    DOI:  https://doi.org/10.1016/j.canlet.2026.218431
  18. Cell Death Discov. 2026 Mar 19.
    The dual impact of GBA1 in disease: from germline mutations in neurological disorders to alterations in cancer.
    Valentina Fantini, Giulia Di Rauso, Valentina Fioravanti, Alessia Ciarrocchi, Francesco Cavallieri, Valentina Sancisi.
      The GBA1 gene encodes the enzyme glucocerebrosidase, which is responsible for lysosomal degradation of the glycosphingolipid glucosylceramide. Biallelic mutations in GBA1 are causative for Gaucher disease, whereas either monoallelic or biallelic mutations are a risk factor for Parkinson's disease. GBA1 mutations, beside reducing enzymatic activity and leading to substrate accumulation, influence a number of molecular and cellular pathways, including lipid homeostasis, endosome-lysosome pathway, endoplasmic reticulum to Golgi protein trafficking, autophagy and mitophagy. Given the critical role of GBA1 in these key pathways for cellular homeostasis, it can be expected that alterations in this enzyme may influence also cancer development and/or pathology, keeping in mind that Gaucher disease is associated with an increased risk of cancer development. Notably, a large fraction of patients affected by different cancer types carry an amplification of the long arm of chromosome 1, that includes the GBA1 gene. Furthermore, GBA1 expression is elevated in different cancer tissues, compared with healthy counterparts and associated with outcome in some cases. In this perspective, we narratively review the main evidence supporting a role for GBA1 in influencing tumorigenesis and we present our analyses on GBA1 amplification and expression throughout different cancer types. Taken together, these data suggest that the presence of a GBA1 germline mutation or a somatic amplification may influence cancer pathogenesis and/or response to therapies through context-dependent mechanisms that are still to be characterized.
    DOI:  https://doi.org/10.1038/s41420-026-03046-6
  19. Neural Regen Res. 2026 Mar 14.
    Cholesterol transporter GRAMD1B in tauopathies: A regulator of lipid homeostasis and tau pathology via autophagy flux.
    Tae Yeon Kim, Marie-Amandine Bonte, Hongjun Fu.
      
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01756
  20. Neural Regen Res. 2026 Mar 14.
    Astrocytic autophagy: From resilience to vulnerability in aging and neurodegeneration.
    Beatriz Martins Fernandes, Michele Siqueira, Flávia Carvalho Alcantara Gomes, Isadora Matias.
      
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01564
  21. FEBS J. 2026 Mar 19.
    Oxidative phosphorylation and mitochondrial dynamics are regulated by Sestrin2 to maintain cellular function.
    Ivo F Machado, Carlos M Palmeira, Anabela P Rolo.
      The stress-inducible protein Sestrin2 (SESN2) has recently emerged as an orchestrator of mitochondrial signaling. The regulation of mitochondria-related pathways, such as aerobic respiration, is thought to be mediated by SESN2, but the underlying mechanisms are not fully understood. Here, we characterized mitochondria in Sesn2-knockdown myoblasts under physiological conditions using oxygen consumption rate measurements, fluorescence microscopy, and protein content analysis. We discovered that SESN2 is essential for sustaining oxidative phosphorylation and maintaining the mitochondrial network organization. SESN2 loss diminished ATP production, decreased the levels of nuclear- and mitochondrial-encoded complex IV subunits, and increased superoxide generation. Moreover, the assessment of mitochondrial distribution in Sesn2-knockdown cells revealed a more fragmented network. This was associated with an increased ratio of short to long optic atrophy 1 (OPA1) forms. Remarkably, disruption of mitochondrial signaling suppressed cellular proliferation and altered both cell and nuclear morphology. In summary, our findings suggest that SESN2 plays an important role in maintaining cellular homeostasis, partly through its impact on mitochondrial function.
    Keywords:  SESN2; mitochondria; mitochondrial dynamics; mitophagy; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/febs.70497
  22. Sci Adv. 2026 Mar 20. 12(12): eadx8715
    Lysosomal down-regulation of the mu opioid receptor is opposed by the Retromer complex.
    Aleksandra Dagunts, Hayden Adoff, Brandon Novy, Lamya Ben Ameur, Monica De Maria, Arpiar Saunders, Braden T Lobingier.
      A critical homeostatic mechanism for regulating G protein-coupled receptor (GPCR) activity is agonist-induced GPCR endocytosis and trafficking to the lysosome for proteolytic down-regulation. The mu opioid receptor (MOR) is a notable example of this type of cellular regulation, where prolonged exposure to high-efficacy opioid drugs causes MOR to traffic to the lysosome. Here, we used functional genomics to identify cellular proteins that control MOR lysosomal down-regulation. We found that the central regulator of MOR postendocytic trafficking is the Retromer complex, which rescues MOR from opioid-induced down-regulation by promoting MOR recycling from endosomes to the plasma membrane. Critically, MOR accesses the Retromer recycling pathway through its noncanonical bileucine recycling motif, and this mechanism controls how MOR is regulated following chronic exposure to opioid drugs. Additionally, we show that this bileucine pathway for Retromer-based recycling is present in other classes of membrane proteins including the glucose transporter GLUT4.
    DOI:  https://doi.org/10.1126/sciadv.adx8715
  23. 3 Biotech. 2026 Apr;16(4): 146
    Neuroprotective effects of DPP-4 inhibitors sitagliptin and vildagliptin in Parkinson's disease via autophagy modulation.
    Maiwulanijiang Yizibula, Yimuranjiang Subuhati, Adili Abudourousuli, Xieraili Tuerxun, Futao Chan, Hengzhi Zhang, Ainiwaer Wumaier, Chimengul Turghun, Mutalifu Aimaiti.
      This study investigates the neuroprotective potential of the dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin and vildagliptin in models of Parkinson's disease (PD). In vitro, sitagliptin (10-80 µM) and vildagliptin (5-40 µM) enhanced mitophagy and modulated autophagy pathway in neuronal cell lines. Sitagliptin (20-80 µM) similarly promoted autophagy in Drosophila larval fat body. In an MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine)-induced mouse model of PD, administration of vildagliptin (15 mg/kg/day) mitigated neuronal loss, reduced microglial activation, and increased tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta and striatum. Network pharmacology and molecular docking analyses identified ten key protein targets, with DPP-4, serine/threonine-protein kinase AKT (AKT1) and glycogen synthase kinase-3 beta (GSK3β) emerging as central nodes. These findings indicate that both drugs engage a multi-target network to modulate autophagy and mitophagy, potentially facilitating the clearance of pathogenic protein aggregates and dysfunctional mitochondria. Together, these results position sitagliptin and vildagliptin as promising autophagy-modifying candidates for disease-modifying PD therapy.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-026-04761-8.
    Keywords:  Autophagy; Disease-modifying therapies; Network pharmacology; Parkinson’s disease; Sitagliptin; Vildagliptin
    DOI:  https://doi.org/10.1007/s13205-026-04761-8
  24. Biochem Biophys Res Commun. 2026 Mar 09. pii: S0006-291X(26)00356-6. [Epub ahead of print]812 153592
    PGC-1α exacerbates apoptosis to induce HIF-1α/BNIP3 mediated mitophagy in heart failure.
    Chengyao Ni, Peng Hu, Yiming Ni.
      Heart failure (HF) is associated with mitochondrial quality control, a key process in quality control. Peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α) regulates mitophagy, but its role in HF remains unclear. This study investigates the role of PGC-1α in HF and its mechanism in mitophagy. Myocardial injury was induced in AC16 cells using pentobarbital, followed by PGC-1α overexpression and treatment with apoptosis inhibitor HY-19696 and mitophagy inhibitor Mdivi-1. A rat HF model was established via aortic constriction, with PGC-1α overexpressed through lentiviral injection. In the cell model, PGC-1α overexpression increased Creatine kinase isoenzyme MB (CK-MB), cardiac troponin T (cTnT), lactate dehydrogenase (LDH) levels, reduced cell viability and mitochondrial membrane potential, enhanced apoptosis and ROS production. These effects were attenuated by apoptosis inhibitor HY-19696. PGC 1α also promoted mitophagy related changes, including an increased LC3 II to LC3 I ratio, and this response was suppressed by Mdivi 1. In the rat model, PGC-1α overexpression aggravated myocardial injury, apoptosis, and damage markers, whereas pharmacological inhibition of apoptosis or mitophagy alleviated these effects. PGC-1α exacerbates HF by promoting apoptosis and enhancing mitophagy through the Hypoxia-inducible factor-1 (HIF-1)/BCL2 interacting protein 3 (BNIP3) pathway. Therefore, PGC-1α changed mitochondrial dynamic homeostasis and promoted HIF-1α/BNIP3-dependent mitophagy in HF.
    Keywords:  Apoptosis; BNIP3; HIF-1α; Heart failure; Mitophagy; PGC-1α
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153592
  25. Exp Neurol. 2026 Mar 18. pii: S0014-4886(26)00072-5. [Epub ahead of print]401 115709
    Rapamycin treatment reduces CD11c+ microglia and increases amyloid plaque load in 5xFAD mice.
    Koliane Ouk, Francisco Fernández-Klett, Eileen Schormann, Andreas Greiner, Anna Santaella, Camila Fernández-Zapata, Chotima Böttcher, Elke Krüger, Josef Priller.
      The mammalian target of rapamycin (mTOR) is involved in immune regulation and in the metabolism of β-amyloid (Aβ) and tau peptides in Alzheimer's disease (AD). In this study, we investigated the effects of the mTOR inhibitor, rapamycin, on central and peripheral immune profiles, proteasome activity, Aβ pathology, and spontaneous exploratory activity and place recognition in the 5xFAD mouse model of amyloid pathology. Using flow cytometry, we found that rapamycin induced changes in immune cell numbers and phenotypes in 5xFAD mice, notably a significant decrease of CD11c+ microglia in cortex and hippocampus of 5xFAD mice. This was associated with increased Aβ plaque load. Concomitantly, we observed a decrease in immunoproteasome content and activity. In peripheral blood, rapamycin treatment resulted in higher percentages of granulocytes, whereas splenic T lymphocytes were reduced. No changes in the open field and modified Y-maze tests were observed following rapamycin treatment in wild-type and 5xFAD mice. Our results reveal detrimental effects of rapamycin on amyloid plaque accumulation and CD11c+ disease-associated microglial subsets in cortex and hippocampus of 5xFAD mice, which is an important finding given two ongoing phase 2 clinical studies of rapamycin treatment in AD.
    Keywords:  Alzheimer's disease; Autophagy; Granulocytes; Lymphocytes; Microglia; Proteasome; Rapamycin; Transgenic mice; Ubiquitin; mTOR signalling pathway
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115709
  26. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2513317123
    The α-synuclein proteostasis network and its translational applications in Parkinson's disease.
    Christine M Lim, Michele Vendruscolo.
      Parkinson's disease (PD) is a debilitating neurodegenerative condition that results in a loss of mobility and muscle control. A neuropathological hallmark of PD is the presence of aberrant inclusions, known as Lewy pathology, of which α-synuclein (α-Syn) is a major component. The accumulation of α-Syn may be due to an imbalance in the proteostasis system regulating α-Syn. To investigate this hypothesis, we delineated the proteostasis network (PN) of α-Syn in the human substantia nigra at the proteomic and transcriptomic level. We then defined an α-Syn proteostasis activity score (PAS) that quantifiably describes the relative activity of the α-Syn PN in promoting or inhibiting α-Syn aggregation. We report a corresponding PAS signature indicative of disease state, age-of-death in PD patients, and brain regional vulnerability to α-Syn aggregation in PD and healthy brains. After establishing the relevance of our network to PD, we developed a transcriptome-derived network model as an operational digital twin of the α-Syn PN in human substantia nigra cells from single-cell data and used it to prioritize candidate targets for PD. We then further showed the application of the α-Syn PN toward facilitating drug repurposing. Overall, this proof-of-concept study illustrates how our computational framework can identify and prioritize putative therapeutic targets and repurposing candidates for PD, providing testable hypotheses for experimental validation.
    Keywords:  Parkinson’s disease; alpha-synuclein; protein homeostasis
    DOI:  https://doi.org/10.1073/pnas.2513317123
  27. FEBS J. 2026 Mar 18.
    Bip1 regulates AMPK signaling in response to endoplasmic reticulum stress.
    Mengdan Zhu, Chuanhai Fu.
      The accumulation of misfolded and unfolded proteins within the endoplasmic reticulum (ER) lumen induces ER stress, which in turn triggers various consequences, such as the unfolded protein response (UPR). AMP-activated protein kinase (AMPK) is also a cellular stress sensor. However, the interplay between AMPK and ER stress remains poorly understood. In this study, we report that in the fission yeast Schizosaccharomyces pombe, the deletion of erd2, a central component for the retrieval of ER-resident proteins, leads to the accumulation of the canonical ER luminal chaperone Bip1 in the cytosol. Moreover, we demonstrate that erd2 deletion increases the levels of the AMPK upstream kinase Ssp1 in a Bip1-dependent manner, thereby promoting AMPK phosphorylation. Intriguingly, although these phenotypes are not dependent on UPR, they can also be caused by ER stress. We further identify multiple E3 ubiquitin ligases that are responsible for the regulation of Ssp1 stability, and Bip1 physically interacts with and stabilises Ssp1 by inhibiting ubiquitination of Ssp1. Additionally, we elucidate that AMPK activation, mediated by the stabilised Ssp1, is required to sustain cell viability, particularly in cells lacking Erd2. Collectively, our findings demonstrate the important role of Erd2 in the maintenance of cellular homeostasis and establish a link between ER stress and AMPK signalling.
    Keywords:  AMPK; Bip1; Erd2; Schizosaccharomyces pombe; Ssp1
    DOI:  https://doi.org/10.1111/febs.70496
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