bims-auttor 2025-07-20 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2025–07–20
thirty papers selected by
Viktor Korolchuk, Newcastle University

Multi-site phosphorylation of BCL2L13 in a TBK1- and AMPK-dependent manner reveals new modes of mitophagy regulation.
Growth Factor-Independent mTORC1 Signaling Promotes Primary Cilia Length via Suppression of Autophagy.
m6A Methylation-Induced Autophagy Impairment by TFEB Regulation in SOD1-G93A ALS Cell Model.
Characterization of WAC interactions with R2TP and TTT chaperone complexes linking glucose and glutamine availability to mTORC1 activity.
A comprehensive analysis of the relationship between inflammasomes and autophagy in human tumors: Recent developments.
High protein does not change autophagy in human peripheral blood mononuclear cells after one hour.
Synergistic Control of Mitochondrial Dynamics and Function by ERAD and Autophagy in Brown Adipocytes.
The Role of S6K1 in Aging and Alzheimer's Disease: Mechanistic Insights and Therapeutic Potential.
Identification of SRSF9 through pooled shRNA screening links BNIP3 splicing to autophagy and metabolic reprogramming in breast cancer.
LINC00622 transcriptionally promotes RRAGD to repress mTORC1-modulated autophagic cell death by associating with BTF3 in cutaneous melanoma.
Treatment of age-related decreases in GTP levels restores endocytosis and autophagy.
JIP4 deficiency causes a lysosomal storage disease arising from impaired cystine efflux.
Restricting intracellular Salmonella proliferation by coordinating p-TBK1 mediated mitophagy and xenophagy.
Laminar Shear Stress Increases the Cytosolic Pool of PINK1 in Endothelial Cells and Enhances Mitophagic Sensitivity Toward Dysfunctional Mitochondria.
Autophagy paradox: Genetic and epigenetic control of autophagy in cancer progression.
Renal tubular VMP1 protects against acute kidney injury via modulating autophagy and autophagy-independent pathway.
ER-phagy Activation by AMFR Attenuates Cardiac Fibrosis Post-Myocardial Infarction via mTORC1 Pathway.
Novel insights into the ULK2-FIP200-AMPK-mediated regulation of autophagy and BCR::ABL degradation in chronic myeloid leukemia.
Mechanism and regulation of mitophagy in liver diseases: a review.
Interplay between MAPK signaling pathway and autophagy in skin aging: mechanistic insights and therapeutic implications.
Membralin Selects Foreign Glycoproteins from the Endoplasmic Reticulum to Lysosomes for Degradation.
NRBP1 pseudokinase binds to and activates the WNK pathway in response to osmotic stress.
Paradoxical mTORC1-Dependent microRNA-mediated Translation Repression in the Nucleus Accumbens of Male Mice Consuming Alcohol Attenuates Glycolysis.
A hypoxia-responsive tRNA-derived small RNA confers renal protection through RNA autophagy.
Sustained Lysosomal Delivery of Enhanced Cy3-Labeled Acid Nanoparticles Restores Lysosomal pH in Retinal Pigment Epithelial Cells and Astrocytes.
PIF4 controls autophagy during hypocotyl response to elevated ambient temperatures via ArpC5 in Arabidopsis.
Proteoglycans are protagonists in autophagy, lymphangiogenesis, and neurodegenerative diseases.
BRMS1 suppresses the PI3K/AKT/mTOR pathway to regulate autophagy in multiple myeloma.
Ursolic Acid Suppresses Colorectal Cancer Through Autophagy-Lysosomal Degradation of β-Catenin.
Lysosomal Enhancement Prevents Infection with PrP Sc , α-Synuclein & Tau Prions.

bioRxiv. 2025 Jul 11. pii: 2025.07.10.663832. [Epub ahead of print]

Multi-site phosphorylation of BCL2L13 in a TBK1- and AMPK-dependent manner reveals new modes of mitophagy regulation.

Hoda Ahmed, Mack B Reynolds, Gary Kasof, Gerald S Shadel, Reuben Shaw.

Mitophagy is a selective autophagic process that eliminates damaged mitochondria via lysosomal degradation, playing a crucial role in maintaining cellular metabolic balance. Mitophagy can occur through two pathways: ubiquitin-dependent and ubiquitin-independent. Recently, we and others have shown that, upon mitochondrial stress, AMP-activated protein kinase (AMPK) contributes to Parkin-mediated, ubiquitin-dependent mitophagy. The ubiquitin-independent pathway involves multiple outer mitochondrial membrane (OMM) "mitophagy receptors" that contain LC3-interacting region (LIR) motifs, including BNIP3, NIX/ BNIP3L, FUNDC1, and BCL2L13. LIR motifs bind Atg8/LC3 family proteins, facilitating the recruitment of the autophagosome membrane to target damaged mitochondria for degradation. The kinase Unc-51 Like autophagy activating kinase 1 (ULK1) phosphorylates the serine preceding the LIR motif in BNIP3, NIX, and FUNDC1, enhancing their binding to LC3 and promoting mitophagy. However, while BCL2L13 has been identified as a ULK1 binding partner, its regulation by phosphorylation remains unclear. We utilized mass spectrometry (MS) to map phosphorylation sites in BCL2L13 following mitochondrial stress and developed phospho-specific antibodies against two sites, Ser261 and Ser275, which were induced after exposure to the mitochondrial uncoupler, CCCP. Endogenous BCL2L13 Ser261 and Ser275 were both phosphorylated in an AMPK-dependent manner in cells and tissues. As neither site matches the established AMPK substrate consensus motif, we sought to identify which kinases directly mediate their phosphorylation downstream of AMPK. Surprisingly, genetic studies revealed that ULK1 is not regulating either site, but instead, TBK1 is controlling Ser275. This work reveals that BCL2L13 is unique amongst mitophagy receptors in being activated by mitochondrial stress and innate immune stimuli in an AMPK- and TBK1-dependent manner.

DOI: https://doi.org/10.1101/2025.07.10.663832
bioRxiv. 2025 May 07. pii: 2025.05.07.652626. [Epub ahead of print]

Growth Factor-Independent mTORC1 Signaling Promotes Primary Cilia Length via Suppression of Autophagy.

Jong Shin, Yann Cormerais, Khaled Tighanimine, Pratima Niroula, Madi Y Cisse, Samuel C Lapp, Krystle C Kalafut, Sandra Schrötter, Brendan D Manning.

The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), as a sensor of growth signals that subsequently controls cell growth, has been predominantly studied in actively proliferating cells. Primary cilia are sensory organelles present on most quiescent cells, where they play essential roles in receiving environmental and developmental signals. Given that ciliated cells are non-proliferative, we investigated whether mTORC1 signaling influences the growth of primary cilia. Here, we show that mTORC1 promotes primary cilia elongation, without effects on ciliogenesis or cell growth, by suppressing autophagy. Inhibition of mTORC1 signaling through pharmacological, nutritional, or genetic interventions gave rise to shortened primary cilia, while activation of the pathway resulted in elongation. Furthermore, pharmacological or genetic inhibition of autophagy, a key downstream process blocked by mTORC1, also elongated primary cilia and rendered them resistant to mTORC1 inhibition. Notably, these mTORC1-mediated effects on primary cilia extend to mouse neurons ex vivo and in vivo. These findings highlight a previously unrecognized role for mTORC1 signaling in the control of primary cilia length that may contribute to diseases where ciliary function is altered, referred to as ciliopathies.

DOI: https://doi.org/10.1101/2025.05.07.652626
Am J Med Genet B Neuropsychiatr Genet. 2025 Jul 17. e33048

m6A Methylation-Induced Autophagy Impairment by TFEB Regulation in SOD1-G93A ALS Cell Model.

Di An, Yuhao Wu, Jingzhe Han, Pingping Fang, Yi Bu, Guang Ji, Jinliang Deng, Xueqin Song.

  We investigate the role of m6A RNA methylation in regulating transcription factor EB (TFEB) and its contribution to mitochondrial autophagy (mitophagy) dysfunction in amyotrophic lateral sclerosis (ALS). ALS cell models were used to analyse mitophagy markers and TFEB expression under METTL3 and TFEB modulation, using RT-qPCR, Western blot, MeRIP, RIP, and immunofluorescence. Elevated m6A methylation and reduced TFEB expression were observed in hSOD1-G93A models. METTL3 overexpression suppressed TFEB expression, leading to impaired mitophagy, while METTL3 knockdown alleviated these effects. MeRIP assays confirmed increased m6A modifications on TFEB mRNA, and RIP assays demonstrated direct interaction between METTL3 and TFEB mRNA. Notably, TFEB overexpression rescued mitophagy dysfunction, whereas TFEB knockdown exacerbated the impairment. METTL3-mediated m6A methylation inhibits mitophagy by downregulating TFEB expression, revealing the m6A-TFEB pathway as a promising therapeutic target for ALS.

Keywords:  METTL3; amyotrophic lateral sclerosis; m6A methylation; mitochondrial autophagy; transcription factor EB (TFEB)

DOI:  https://doi.org/10.1002/ajmg.b.33048
FEBS Open Bio. 2025 Jul 13.

Characterization of WAC interactions with R2TP and TTT chaperone complexes linking glucose and glutamine availability to mTORC1 activity.

Sofía Cabezudo, Natalia Cuervo, Carmen García-Martín, Andrés López-Perrote, Clara Reglero, Adrián Maqueda-Real, Ana González-Corpas, Marina Serna, Diego Megías, Alejo Efeyan, Solip Park, Oscar Llorca.

  TELO2-TTI1-TTI2 (TTT) and R2TP are multi-subunit chaperones that cooperate with HSP90 to assemble matured complexes of the PIKK family of kinases, including mTOR complex 1 (mTORC1). WAC, a protein previously implicated in transcription, H2B ubiquitination, and autophagy, was recently identified as a regulator of mTORC1 in response to glucose and glutamine availability, acting in concert with R2TP and TTT. However, the molecular basis of the interactions of WAC with R2TP and TTT and their role in mTORC1 regulation remains poorly defined. Here, we characterized the interactions of WAC with mTOR, R2TP, and TTT and how these are affected by nutrient conditions. Using purified proteins, we establish that WAC directly binds to mTOR-mLST8, R2TP, and TELO2, but not TTI1 and TTI2. In cells, WAC is part of complexes containing components of mTORC1, R2TP, and TTT, and these associations are modulated by nutrient availability. Notably, WAC and TELO2 strongly associate with mTOR under glucose and glutamine deprivation, and these interactions are weakened minutes after nutrient refeeding. These dynamics correlate with changes in mTORC1 activity. Transcriptomic and proteomic analysis shows that WAC, mTOR, R2TP, and TTT are co-expressed across several human cancers, supporting that WAC is part of a functional pathway with mTOR, R2TP, and TTT. Together, our findings reveal the formation and disassembly of a WAC complex with mTOR and TELO2 that contributes to regulate mTORC1 in response to glucose and glutamine availability.

Keywords:  R2TP; RUVBL1‐RUVBL2; TELO2; WAC; mTORC1

DOI:  https://doi.org/10.1002/2211-5463.70085
J Cell Commun Signal. 2025 Sep;19(3): e70035

A comprehensive analysis of the relationship between inflammasomes and autophagy in human tumors: Recent developments.

Sai Liu, Jingzhou Zhang.

  Autophagy and inflammasomes are essential cellular mechanisms that maintain homeostasis, regulate immune responses, and influence disease progression, especially in cancer. Autophagy, a lysosome-mediated process, removes damaged organelles and misfolded proteins, allowing cells to adapt to stress. This involves autophagosome formation, fusion with lysosomes, and subsequent degradation of cellular cargo. In contrast, inflammasomes are multiprotein complexes of the innate immune system that detect pathogenic signals and cellular stress, initiating inflammatory cytokine release to facilitate tissue repair. Notably, both pathways play dual roles in cancer: Although they help preserve cellular integrity and suppress tumorigenesis, they may also promote tumor survival under adverse conditions. This review explores the molecular mechanisms underlying autophagy and inflammasome activity, emphasizing their complex interplay and regulatory networks within the tumor microenvironment.

Keywords:  autophagy; immunity; inflammasomes; tumor

DOI:  https://doi.org/10.1002/ccs3.70035
JCI Insight. 2025 Jul 15. pii: e188845. [Epub ahead of print]

High protein does not change autophagy in human peripheral blood mononuclear cells after one hour.

Sanjna Singh, Célia Fourrier, Kathryn J Hattersley, Leanne K Hein, Jemima Gore, Alexis Martin, Linh Vp Dang, Barbara King, Rachael A Protzman, Paul J Trim, Leonie K Heilbronn, Julien Bensalem, Timothy J Sargeant.

  Autophagy is a catabolic quality control pathway that has been linked to neurodegenerative disease, atherosclerosis and ageing, and can be modified by nutrient availability in preclinical models. Consequently, there is immense public interest in stimulating autophagy in people. However, progress has been hampered by the lack of techniques to measure human autophagy. As a result, several key concepts in the field, including nutritional modulation of autophagy, have yet to be validated in humans. We conducted a single arm pre-post study in 42 healthy individuals, to assess whether an acute nutritional intervention could modify autophagy in humans. Two blood samples were collected per participant: after a 12 h overnight fast and 1 h post-consumption of a high protein meal. Autophagy turnover was assessed using a physiologically relevant measure of autophagic flux in peripheral blood mononuclear cells. A lysosomal inhibitor was added directly to whole blood, with the resulting build-up of autophagy marker LC3B-II designated as flux, and measured quantitatively via ELISA. Notably, consumption of a high protein meal had no impact on autophagy, with no differences between overnight fasting and postprandial autophagic flux. We observed sexual dimorphism in autophagy, with females having higher autophagic flux compared to males (p = 0.0031). Exploratory analyses revealed sex-specific correlations between autophagy, insulin and glucose signalling. Importantly, our findings show that an acute nutritional intervention (overnight fasting followed by consumption of a protein-rich meal) does not change autophagic flux in humans, highlighting the need to conduct further autophagy studies in humans.

Keywords:  Autophagy; Cell biology; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.188845
bioRxiv. 2025 Jun 15. pii: 2025.06.14.659625. [Epub ahead of print]

Synergistic Control of Mitochondrial Dynamics and Function by ERAD and Autophagy in Brown Adipocytes.

Xinxin Chen, Siwen Wang, Mauricio Torres, Sijie Hao, Shengyi Sun, Ling Qi.

Mitochondrial quality control is essential for maintaining cellular energy homeostasis, particularly in brown adipocytes where dynamic mitochondrial remodeling supports thermogenesis. Although the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD) pathway and autophagy are two major proteostatic systems, how these pathways intersect to regulate mitochondrial integrity in metabolically active tissues remains poorly understood. Here, using adipocyte-specific genetic mouse models combined with high-resolution 2D and 3D ultrastructural imaging technologies, we reveal an unexpected synergy between SEL1L-HRD1 ERAD and autophagy in maintaining mitochondrial structure and function in brown adipocytes. Loss of ERAD alone triggers compensatory autophagy, whereas combined deletion of both pathways (double knockout, DKO) results in severe mitochondrial abnormalities, including the accumulation of hyperfused megamitochondria penetrated by ER tubules, even under basal room temperature conditions. These phenotypes are absent in mice lacking either pathway individually or in SEL1L-IRE1α DKO, highlighting the pathway-specific coordination between ERAD and autophagy. Mechanistically, dual loss of ERAD and autophagy induces ER expansion, excessive ER-mitochondria contact, upregulation of mitochondria-associated membrane (MAM) tethering proteins, impaired calcium transfer, and defective mitochondrial turnover. As a result, DKO adipocytes accumulate dysfunctional mitochondria, exhibit respiratory deficits, and fail to sustain thermogenesis. Collectively, our study uncovers a cooperative and previously unrecognized mechanism of mitochondrial surveillance, emphasizing the critical role of ERAD-autophagy crosstalk in preserving mitochondrial integrity and thermogenic capacity in brown fat.
One-sentence summary: Our study uncovers a previously unrecognized synergy between SEL1L-HRD1 ERAD and autophagy that is essential for preserving mitochondrial integrity and thermogenic capacity in brown adipocytes, revealing new opportunities for targeting mitochondrial dysfunction in metabolic disease.

DOI: https://doi.org/10.1101/2025.06.14.659625
Int J Mol Sci. 2025 Jun 20. pii: 5923. [Epub ahead of print]26(13):

The Role of S6K1 in Aging and Alzheimer's Disease: Mechanistic Insights and Therapeutic Potential.

Salvatore Oddo, Marika Lanza, Giovanna Casili, Antonella Caccamo.

  Aging is the greatest risk factor for Alzheimer's disease (AD), but the mechanisms connecting the two remain unclear. The mammalian target of rapamycin (mTOR) pathway, particularly its downstream effector S6 kinase 1 (S6K1), has emerged as a key regulator of aging and neurodegeneration. S6K1 controls translation, autophagy, and mitochondrial function-processes disrupted in both aging and AD. This review examines how S6K1 influences mitochondrial metabolism, autophagy, and metabolic dysfunction in aging. We also discuss its role in the nervous system, including effects on synaptic plasticity, memory, glial activation, and neuroinflammation. In AD, S6K1 contributes to amyloid and tau pathology by regulating translation of BACE1 and tau, and its hyperactivation is linked to synaptic deficits and cognitive decline. We further explore therapeutic strategies targeting S6K1, which have shown benefits for lifespan extension and neuroprotection in preclinical models. Finally, we consider the emerging link between S6K1 and necroptosis, a form of programmed cell death implicated in AD-related neuronal loss. Together, these findings highlight S6K1 as a promising target for interventions aimed at slowing aging and mitigating AD pathogenesis.

Keywords:  Alzheimer’s disease; S6K1; aging

DOI:  https://doi.org/10.3390/ijms26135923
J Biol Chem. 2025 Jul 15. pii: S0021-9258(25)02332-4. [Epub ahead of print] 110482

Identification of SRSF9 through pooled shRNA screening links BNIP3 splicing to autophagy and metabolic reprogramming in breast cancer.

Anchala Pandey, B Jithin, Srinivas Abhishek Mutnuru, Atul Samaiya, Sanjeev Shukla.

  Autophagy is a critical catabolic process that maintains cellular homeostasis, yet the role of alternative splicing in regulating hypoxia-induced autophagy remains largely unexplored. Here, through a pooled shRNA screen of RNA binding proteins (RBPs) in hypoxic breast cancer cells, we identified the splicing factor SRSF9 as a key regulator. We found that SRSF9 expression is significantly reduced under hypoxia, while its restoration diminishes autophagosome formation. SRSF9 directly controls the alternative splicing of BNIP3 by binding to its third exon, generating two functionally distinct isoforms. The full-length isoform, BNIP3-FL, promotes canonical autophagy by interacting with the BCL-2-BECN1 complex. In contrast, the truncated isoform, BNIP3-Δ3, lacks this function and instead promotes a metabolic shift to the Warburg effect. This metabolic reprogramming by BNIP3-Δ3 enhances breast cancer progression, including proliferation and invasion, and confers chemoresistance to paclitaxel. Collectively, our study identifies a previously unreported mechanism where SRSF9 governs the balance between autophagy and the Warburg effect via BNIP3 alternative splicing, thereby establishing a critical link between splicing regulation, metabolic adaptation, and therapeutic resistance in breast cancer.

Keywords:  BNIP3-FL; BNIP3-Δ3; High Content Screening; Hypoxia; Paclitaxel; SRSF9

DOI:  https://doi.org/10.1016/j.jbc.2025.110482
Cell Death Dis. 2025 Jul 12. 16(1): 515

LINC00622 transcriptionally promotes RRAGD to repress mTORC1-modulated autophagic cell death by associating with BTF3 in cutaneous melanoma.

Can Li, Ke Wang, Lei Zhao, Jieyu Liu, Yi Jin, Chunting Zhang, Minna Xu, Min Wang, Yanjie Kuang, Jun Liu, Liang Zhou, Qian Wen.

Autophagy plays critical and complicated roles in tumors. As the central hub of nutrient signaling and cell growth, mTOR constitutes mTORC1 to be the main gateway for modulating autophagy. Yet, the regulatory mechanisms of mTORC1-regulated autophagy in tumors are not fully deciphered. Here, we report a novel long noncoding RNA, LINC00622, which modulates mTORC1-regulated autophagy in cutaneous melanoma. Functionally, LINC00622 acts as a pro-oncogenic factor to promote proliferation, colony formation, migration and invasion in melanoma while suppressing cell death. Mechanistically, LINC00622 associates with and recruits BTF3 to transcriptionally enhance RRAGD expression for activating mTORC1 and thus inhibiting autophagic cell death, which contributes to the development of cutaneous melanoma. Our findings not only demonstrated the oncogenic role of LINC00622 via RRAGD/mTORC1 axis to repress autophagic cell death in cutaneous melanoma, but also offer novel treatment targets for melanoma therapy.

DOI: https://doi.org/10.1038/s41419-025-07828-1
bioRxiv. 2025 Jun 12. pii: 2025.06.09.658689. [Epub ahead of print]

Treatment of age-related decreases in GTP levels restores endocytosis and autophagy.

R A Santana, J M McWhirt, G J Brewer.

Age-related declines in neuronal bioenergetic levels may limit vesicular trafficking and autophagic clearance of damaged organelles and proteins. Age-related ATP depletion would impact cognition dependent on ionic homeostasis, but limits on proteostasis powered by GTP are less clear. We used neurons isolated from aged 3xTg-AD Alzheimer's model mice and a novel genetically encoded fluorescent GTP sensor (GEVAL) to evaluate live GTP levels in situ. We report an age-dependent reduction in ratiometric measurements of free/bound GTP levels in living hippocampal neurons. Free-GTP co-localized in the mitochondria decreased with age accompanied by the accumulation of free-GTP labeled vesicular structures. The energy dependence of autophagy was demonstrated by depletion of GTP with rapamycin stimulation, while bafilomycin inhibition of autophagy raised GTP levels. 24 hr. supplementation of aged neurons with the NAD precursor nicotinamide and the Nrf2 redox modulator EGCG restored GTP levels to youthful levels and mobilized endocytosis and lysosomal consumption for autophagy via the respective GTPases Rab7 and Arl8b. This vesicular mobilization promoted the clearance of intraneuronal Aβ aggregates and lowered protein oxidative nitration in AD model neurons. Our results reveal age- and AD-related neuronal GTP energy deficits that impair autophagy and endocytosis. GTP deficits were remediated by an external NAD precursor together with a Nrf2 redox modulator which suggests a translational path.

DOI: https://doi.org/10.1101/2025.06.09.658689
bioRxiv. 2025 Jun 08. pii: 2025.06.06.657909. [Epub ahead of print]

JIP4 deficiency causes a lysosomal storage disease arising from impaired cystine efflux.

Layla M Nassar, Xiaojian Shi, Agnes Roczniak-Ferguson, Hongying Shen, Shawn M Ferguson.

Lysosomes break down macromolecules, clear cellular waste and recycle nutrients such as cystine. We describe a novel mechanism whereby JIP4 regulates lysosomal cystine storage by controlling the abundance of cystinosin (CTNS), the transporter responsible for lysosomal cystine efflux. To this end, JIP4, previously characterized as a motor adaptor and kinase signaling scaffold, suppresses TMEM55B-dependent ubiquitylation of CTNS. Loss of JIP4 reduces CTNS protein levels, leading to lysosomal cystine accumulation and lysosomal storage defects that phenocopy loss of CTNS in both human cells and the renal proximal tubules of JIP4 knockout mice. These phenotypes mirror cystinosis, the lysosomal storage disease caused by CTNS loss-of-function. Our findings thus reveal a fundamental process that controls the efflux of lysosomal cystine and has relevance to understanding human disease arising from JIP4 mutations.

DOI: https://doi.org/10.1101/2025.06.06.657909
Autophagy. 2025 Jul 14.

Restricting intracellular Salmonella proliferation by coordinating p-TBK1 mediated mitophagy and xenophagy.

Jun Li, Yang Yang, Yao Ge, Xinyu Zhang, Haozhen Liu, Yinfeng Chen, Ying Yang, Zhenlong Wu.

  Mitophagy is essential for eliminating dysfunctional mitochondria and is closely implicated in the immune evasion of several pathogens, including S. typhimurium. However, the specific mechanisms regarding the interaction between S. typhimurium and host cells in relation to mitophagy and xenophagy and their contribution to pathogen survival are unclear. Herein, using both in vitro and in vivo systems, we found that S. typhimurium escaped host innate immunity by repressing mitophagy and xenophagy to facilitate its intracellular replication. Moreover, we identified a novel xenophagy modulator, fisetin that could activate mitophagy to restrict intracellular S. typhimurium replication in RAW264.7 and bone marrow-derived macrophages, which was abolished by mitophagy inhibitor Mdivi-1. RNA-Seq transcriptome and metabolomics analysis demonstrated the effectiveness of fisetin in alleviating S. typhimurium infection. Confocal microscopy analysis revealed that fisetin-induced mitophagy promoted xenophagy, whereas inhibiting mitophagy repressed xenophagy and facilitated the survival of S. typhimurium. Our study further demonstrates that fisetin-induced mitophagy requires the recruitment of phosphorylation of TBK1 to mitochondria, which is a protein implicated in mitophagy and xenophagy. Additionally, fisetin improved the body weight loss, relative spleen, kidney, and liver weights, hepatic damage, and S. typhimurium load, all of which were abrogated by Mdivi-1 or Pink1 siRNA treatment in S. typhimurium-infected mice. Collectively, our results suggest that S. typhimurium induces mitochondrial damage whilst inhibiting mitophagy, while fisetin promotes xenophagy and restrains S. typhimurium survival by facilitating Pink1-Parkin mediated mitophagy and p-TBK1 mitochondrial recruitment. Fisetin proves effective as a xenophagy enhancer in reducing intracellular Salmonella burden.

Keywords:  Immune escape; Mitophagy; Salmonella; TBK1; Xenophagy

DOI:  https://doi.org/10.1080/15548627.2025.2534298
bioRxiv. 2025 Jun 26. pii: 2025.06.21.660867. [Epub ahead of print]

Laminar Shear Stress Increases the Cytosolic Pool of PINK1 in Endothelial Cells and Enhances Mitophagic Sensitivity Toward Dysfunctional Mitochondria.

Soon-Gook Hong, Junchul Shin, Jason Saredy, Soo Young Choi, Hong Wang, Joon-Young Park.

Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) is an essential molecule in mitophagy process in mammalian cells. Mutation or deficiency of PINK1 has been closely related to several disease conditions. The purpose of this study was to determine PINK1 expression levels and subcellular localization under exercise-mimic laminar shear stress (LSS) condition in human aortic endothelial cells (HAECs) or in exercising mice, and its implication on endothelial homeostasis and cardiovascular disease (CVD) prevention. First, LSS significantly elevated both full-length PINK1 (FL-PINK1) mRNA and protein expressions in ECs. Mitochondrial fractionation assays and confocal microscopic analysis showed reduced FL-PINK1 accumulation on mitochondria with an increase in a cytosolic pool of FL-PINK1 under LSS. Mitophagy flux, determined by a mtKeima probe, decreased with intact mitochondrial morphology and membrane potential under LSS, suggesting that elevated cytosolic PINK1 is not utilized for immediate mitophagy inductions. However, increased cytosolic PINK1 seems to elevate mitophagic sensitivity toward dysfunctional mitochondria in pathological conditions. LSS-preconditioned ECs showed lower angiotensin II (AngII)-induced mtDNA lesions and displayed rapid Parkin recruitment and mitophagy induction in response to mitochondrial uncoupler (CCCP) treatment. Exercise-preconditioned mice, a physiological LSS-enhanced model, showed elevated PINK1 expression in ECs of the thoracic aorta compared to sedentary control. In addition, exercise enhanced AngII-induced mitophagy induction in ECs and reduced AngII-induced mtDNA lesion formation in the mouse aorta. Taken together, LSS increases a cytosolic pool of FL-PINK1, which may elevate the mitophagic sensitivity toward dysfunctional mitochondria in ECs.

DOI: https://doi.org/10.1101/2025.06.21.660867
Cancer Lett. 2025 Jul 09. pii: S0304-3835(25)00477-X. [Epub ahead of print]630 217909

Autophagy paradox: Genetic and epigenetic control of autophagy in cancer progression.

Chandra Sekhar Bhol, Prakash Kumar Senapati, Rakesh Kumar Kar, Grace Chew, Kewal Kumar Mahapatra, E Hui Clarissa Lee, Alan Prem Kumar, Sujit Kumar Bhutia, Gautam Sethi.

  Autophagy is a highly regulated, evolutionarily conserved process of self-digestion controlled by autophagy-related (ATG) genes. It involves the lysosomal degradation of cargoes, including cytoplasmic organelles, misfolded proteins, and toxic aggregates, to enrich cellular nutrient pools and reduce oxidative stress. In normal cells, basal autophagy occurs to maintain cellular homeostasis, which changes during tumor initiation, progression, and malignant transformation. The alteration in autophagy in cancer remains unclear and under-explored. Research indicates that genetic regulations, such as gene mutations, gene polymorphisms, or epigenetic modifications, including DNA methylation, histone modification, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs), regulate ATGs, orchestrating the fluctuating nature of autophagy in cancer. Many studies describe the paradoxical role of autophagy in cancer, portraying it as a double-edged sword depending on the context, oscillating between promoting cell survival and inducing cell death-the dual roles in preventing tumor initiation and supporting tumor progression place autophagy at the centre of controversy. Recent findings suggest that autophagy is regulated at the intrinsic cellular level and within the tumor microenvironment. Thus, identifying the molecules, mediators, and mechanisms associated with the regulation of autophagy during tumor development, maintenance, therapy resistance, and dormancy could open new research avenues to enhance the efficacy of cancer therapeutics. Furthermore, this review encompasses preclinical studies and clinical trials, highlighting the effectiveness of modulating autophagy in cancer therapy.

Keywords:  Autophagy; Cancer; DNA methylation; Gene polymorphism; Genetic mutation; Histone modification; lncRNA; miRNA

DOI:  https://doi.org/10.1016/j.canlet.2025.217909
Autophagy. 2025 Jul 14.

Renal tubular VMP1 protects against acute kidney injury via modulating autophagy and autophagy-independent pathway.

Wenwen Yang, Meng Jia, Fenglian Zhou, Mingchao Zhang, Shuang Qu, Caihong Zeng, Xiaodong Zhu, Shouyong Gu, Ji Xuan, Zhihong Liu, Ke Zen.

  Macroautophagy/autophagy activation protects renal proximal tubular epithelial cells (PTECs) against acute kidney injury (AKI) induced by various challenges. The mechanism that regulates autophagy in PTECs, however, remains incompletely understood. Here, we report that VMP1 (vacuole membrane protein 1) plays an essential role in enabling PTECs to maintain high autophagic flow under AKI conditions. VMP1 in PTECs is strongly upregulated in AKI patients but not chronic kidney disease patients. The rapid elevation of VMP1 expression in PTECs during AKI is validated in mouse AKI models induced by cisplatin or ischemia-reperfusion injury (IRI). PTECs-specific vmp1-knockout mice (vmp1-cKO) display more severe renal injuries when challenged with cisplatin or IRI. In line with this, aging vmp1-cKO mice spontaneously develop defective calcium metabolism and display significant tubular damage. In contrast, adenovirus-mediated Vmp1 expression in renal tubular rescues IRI or cisplatin-induced renal tubular injury. Mechanistically, the level and distribution pattern of VMP1 are associated with the autophagy markers MAP1LC3/LC3 and SQSTM1, and VMP1 facilitates the formation of renal tubular cell autophagosomes. VMP1 deficiency also results in the accumulation of lipid droplets in renal tubular cells. Our studies thus reveal a critical role of VMP1 in protecting against AKI via facilitating tubular cell autophagic flux and lipid metabolism.

Keywords:  Acute kidney injury; cisplatin; ischemia-reperfusion injury; lipid droplet; proximal tubular cells; vacuole membrane protein 1

DOI:  https://doi.org/10.1080/15548627.2025.2533306
Adv Sci (Weinh). 2025 Jul 17. e04552

ER-phagy Activation by AMFR Attenuates Cardiac Fibrosis Post-Myocardial Infarction via mTORC1 Pathway.

Zhixiang Wang, Kaifan Niu, Wei Liu, Xinyun Wang, Boshen Yang, Taixi Li, Yizhi Chen, Yuanyuan Jin, Yu Chen, Yangyi Lin, Xian Jin.

  Progressive cardiac fibrosis post myocardial infarction (MI) drives pathological remodeling and heart failure, yet the role of endoplasmic reticulum-selective autophagy (ER-phagy) in this process remains unclear. Autocrine Motility Factor Receptor (AMFR) is a recently identified ER-phagy regulator, whose function under myocardial pathology remains poorly understood. Here, it is found that FAM134B-mediated ER-phagy activity is elevated in fibrotic mouse heart tissues post-MI and in cardiac fibroblasts stimulated by TGF-β1. AMFR knockout in mice aggravated cardiac fibrosis post-MI and worsened cardiac function, with scRNA-seq analysis demonstrating that AMFR-null cardiac fibroblasts exhibit a myofibroblast phenotype. Simultaneously, AMFR overexpression in cardiac fibroblasts reduces the expression of profibrogenic proteins in response to TGF-β1 stimulation. AMFR regulates ER-phagy flux and turnover of FAM134B, which leads to the suppression of cardiac fibroblasts activation. Mechanistically, AMFR catalyzed K27-linked (predominant) and K33-linked ubiquitination of FAM134B and enhanced ER-phagy flux, thereby inhibiting the phosphorylation of mTORC1 downstream targets such as S6K1 and 4E-BP. These findings highlight the therapeutic potential of AMFR-driven ER-phagy in suppressing cardiac fibrosis post-MI.

Keywords:  AMFR; ER‐phagy; FAM134B; fibroblast activation; mTORC1; myocardial infarction

DOI:  https://doi.org/10.1002/advs.202504552
Biochem Biophys Res Commun. 2025 Jul 13. pii: S0006-291X(25)01058-7. [Epub ahead of print]778 152343

Novel insights into the ULK2-FIP200-AMPK-mediated regulation of autophagy and BCR::ABL degradation in chronic myeloid leukemia.

Daisuke Koyama, Naoki Yamamoto, Takaaki Abe, Kengo Suzuki, Yuki Sato, Manabu Suzuki, Naoya Shibayama, Takayuki Ikezoe.

  Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by the BCR::ABL fusion tyrosine kinase. AMP-activated protein kinase (AMPK) plays a pivotal role in regulating cellular energy homeostasis, ensuring an adequate ATP supply for CML cell proliferation. ULK1, a well-known AMPK substrate, is a critical serine/threonine kinase in the autophagy initiation complex. ULK2, a paralog of ULK1, shares approximately 50 % amino acid sequence homology and has been reported to function complementarily with ULK1. However, emerging evidence suggests that ULK2 also has unique functions distinct from those of ULK1. Public RNA sequencing data revealed that ULK2 expression is significantly lower in hematopoietic cells compared to other tissues. To explore the function of ULK2, we performed in vitro assays using 293FT cells, which endogenously express high levels of ULK2. Mass spectrometry analysis demonstrated that ULK2 forms a stable complex with FIP200, which in turn interacts specifically with the AMPK α1 and γ1 subunits. Furthermore, shRNA-mediated knockdown of ULK2 induced AMPK activation and promoted the cytoplasmic accumulation of ULK1 and FIP200, thereby inducing autophagy in CML cells. Although autophagy typically acts as a cytoprotective mechanism, in this context, the autophagy-dependent degradation of BCR::ABL induced cell death. These findings reveal a novel regulatory axis involving ULK2, FIP200, AMPK, and autophagy, suggesting a unique role for ULK2 in CML pathophysiology and offering potential therapeutic insights.

Keywords:  AMPK; Autophagy; Chronic myeloid leukemia; FIP200; ULK2

DOI:  https://doi.org/10.1016/j.bbrc.2025.152343
Front Cell Dev Biol. 2025 ;13 1614940

Mechanism and regulation of mitophagy in liver diseases: a review.

Sen Liu, Libo Wang, Liuyang Zhu, Tianyu Zhao, Pinsheng Han, Fengying Yan, Xiaoliang Wang, Chunli Li, Ze Wang, Bao-Feng Yang.

  Mitochondria are vital for the proper operation of healthy eukaryotic cells. Mitophagy, a specialized form of autophagy that targets damaged or surplus mitochondria, plays a key role in both the normal functioning and disease-related processes within the liver. This review aims to explore the main mechanisms underlying the initiation of mitophagy and its importance in various liver conditions, such as alcoholic liver disease, drug-induced liver injury, non-alcoholic fatty liver disease, viral hepatitis, and cancer. Gaining insight into these mechanisms can help overcome the obstacles related to harnessing mitophagy as a therapeutic strategy in clinical practice.

Keywords:  DILI; NAFLD; liver disease; mitochondria; mitophagy

DOI:  https://doi.org/10.3389/fcell.2025.1614940
Front Cell Dev Biol. 2025 ;13 1625357

Interplay between MAPK signaling pathway and autophagy in skin aging: mechanistic insights and therapeutic implications.

Xu Liu, Bo Chen, Xuefeng Liu, Xiaoqing Zhang, Jingdong Wu.

  Skin aging manifests as structural degradation, functional decline, and heightened disease susceptibility. Central to this process is the overactivation of the mitogen-activated protein kinase (MAPK) signaling pathway triggered by reactive oxygen species (ROS). Autophagy, a lysosomal degradation mechanism essential for maintaining cellular homeostasis, demonstrates context-dependent duality in skin aging by mediating cytoprotective effects and stress-induced dysfunction. Emerging evidence highlights that the interplay between MAPK signaling and autophagy critically modulates skin aging progression. Despite its therapeutic potential, the lack of effective targeting strategies severely hinders clinical translation. Therefore, this review synthesizes current evidence on MAPK-autophagy interplay across key cutaneous cell populations, namely, keratinocytes, fibroblasts, and melanocytes (including melanoma), revealing cell-type-specific regulatory networks that influence skin aging. Subsequently, we explore the therapeutic potential of natural bioactive compounds targeting this interplay to accelerate the translation of evidence into the progression of strategies for combating skin aging.

Keywords:  MAPK; autophagy; interplay; natural bioactive compounds; skin aging

DOI:  https://doi.org/10.3389/fcell.2025.1625357
Res Sq. 2025 Jun 23. pii: rs.3.rs-6498082. [Epub ahead of print]

Membralin Selects Foreign Glycoproteins from the Endoplasmic Reticulum to Lysosomes for Degradation.

Yong-Hui Zheng, Jing Zhang, Xiaoran Lu, Sunan Li, Tao Wang, Iqbal Ahmad.

The endoplasmic reticulum (ER) plays a central role in protein synthesis and folding. Membralin is a multi-pass membrane protein involved in ER-associated degradation (ERAD). Here, we demonstrate that Membralin assembles a protein degradation machinery across the ER membrane, specifically targeting class I fusion proteins expressed by major human viruses. Membralin interacts with MAN1B1 and p97/VCP through its luminal and cytoplasmic loops, respectively. Importantly, Membralin also contains an LC3-interacting region (LIR) in its cytoplasmic tail. The expression of these viral glycoproteins induces ER stress, prompting MAN1B1 to trim mannose residues extensively. Subsequently, Membralin recruits p97/VCP and initiate ER-phagy via its LIR, leading to degradation. This pathway specifically recognizes dense N -glycans and is selective, as it does not degrade misfolded domestic proteins. Collectively, our study reveals a cell-autonomous immunity inside the ER orchestrated by Membralin, underscoring its important role in the clearance of foreign glycoproteins to maintain cellular homeostasis.

DOI: https://doi.org/10.21203/rs.3.rs-6498082/v1
Sci Adv. 2025 Jul 18. 11(29): eadv4636

NRBP1 pseudokinase binds to and activates the WNK pathway in response to osmotic stress.

Ramchandra V Amnekar, Toby Dite, Pawel Lis, Sebastian Bell, Fiona Brown, Clare Johnson, Stuart Wilkinson, Samantha Raggett, Mark Dorward, Mel Wightman, Thomas Macartney, Renata F Soares, Frederic Lamoliatte, Dario R Alessi.

WNK family kinases are regulated by osmotic stress and control ion homeostasis by activating SPAK and OXSR1 kinases. Using a proximity labeling approach, we found that osmotic stress promotes the association of WNK1 with the NRBP1 pseudokinase and TSC22D2/4 adaptor proteins, results that are confirmed by immunoprecipitation, mass spectrometry, and immunoblotting studies. NRBP1 pseudokinase is closely related to WNK isoforms and contains a RΦ-motif-binding conserved C-terminal (CCT) domain, like the CCT domains in WNKs, SPAK, and OXSR1. Knockdown or knockout of NRBP1 markedly inhibited basal as well as sorbitol-induced activation of WNK1 and downstream components. We demonstrate that recombinant NRBP1 can directly induce the activation of WNK4 in vitro. AlphaFold-3 modeling predicts that WNK1, SPAK, NRBP1, and TSC22D4 form a complex, in which two TSC22D4 RΦ-motifs interact with the CCTL1 domain of WNK1 and the CCT domain of NRBP1. Our data indicate that NRBP1 and likely its close homolog NRBP2 function as an upstream activator of the WNK pathway.

DOI: https://doi.org/10.1126/sciadv.adv4636
Nat Commun. 2025 Jul 14. 16(1): 6116

Paradoxical mTORC1-Dependent microRNA-mediated Translation Repression in the Nucleus Accumbens of Male Mice Consuming Alcohol Attenuates Glycolysis.

Yann Ehinger, Sophie Laguesse, Khanhky Phamluong, Alexandra Salvi, Yoshitaka J Sei, Zachary W Hoisington, Drishti Soneja, Sowmya Gunasekaran, Ken Nakamura, Dorit Ron.

mTORC1 promotes protein translation, learning and memory, and neuroadaptations that underlie alcohol use disorder (AUD). The mechanisms underlying alcohol-mediated mTORC1-dependent neuroadaptations that drive AUD are not well understood. We report that activation of mTORC1 in the nucleus accumbens (NAc) D1 neurons of male mice consuming alcohol results in paradoxical mTORC1-dependent repression of translation of transcripts, including Aldolase A, an essential enzyme in glycolysis. We further show that mTORC1-dependent Aldolase A translation repression in D1 neurons is mediated through upregulation of miR-34a-5p expression. Alcohol-mediated mTORC1 repression of Aldolase A translation in D1 neurons inhibits glycolysis in the NAc. Finally, we report that overexpression of miR-34a-5p in D1 NAc neurons increases, whereas systemic administration of L-lactate, the final product of glycolysis, attenuates excessive alcohol intake. Our data suggest that alcohol promotes paradoxical actions of mTORC1 on translation and glycolysis which in turn drive excessive alcohol use.

DOI: https://doi.org/10.1038/s41467-025-60337-9
Science. 2025 Jul 17. eadp5384

A hypoxia-responsive tRNA-derived small RNA confers renal protection through RNA autophagy.

Guoping Li, Lingfei Sun, Cuiyan Xin, Tian Hao, Prakash Kharel, Aidan C Manning, Christopher L O'Connor, Henry Moore, Shuwen Lei, Priyanka Gokulnath, Xinyu Yang, Ritin Sharma, Krystine Garcia-Mansfield, Priyadarshini Pantham, Chunyang Xiao, Hanna Y Wang, Emeli Chatterjee, Seungbin Yim, Leo B Ren, Michail Spanos, Hua Zhu, Haobo Li, Ji Lei, James F Markmann, Louise C Laurent, John J Rossi, Oluwaseun Akeju, Quanhu Sheng, Ravi V Shah, William A Goddard, Todd M Lowe, Patrick Pirrotte, Markus Bitzer, Pavel Ivanov, Joseph V Bonventre, Saumya Das.

Transfer RNA-derived small RNAs (tsRNAs, or tDRs) perform a range of cellular functions. Here, we showed that a hypoxia-induced tDR, derived from the 3' end of tRNA-Asp-GTC (tRNA-Asp-GTC-3'tDR), activated autophagic flux in kidney cells, while its silencing blocked autophagic flux. Functional gain/loss-of-function studies in murine kidney disease models demonstrated a significant reno-protective function of tRNA-Asp-GTC-3'tDR. Mechanistically, tRNA-Asp-GTC-3'tDR assembled stable G-quadruplex structures and sequestered pseudouridine synthase PUS7, preventing catalytic pseudouridylation of histone mRNAs. The resulting pseudouridylation deficiency directed histone mRNAs to the autophagosome-lysosome pathway, triggering RNA autophagy. This tDR-induced RNA autophagy pathway was activated during murine and human kidney diseases, suggesting clinical relevance. Thus, tRNA-Asp-GTC-3'tDR plays a role in regulating RNA autophagy, which helps to maintain homeostasis in kidney cells and protects against kidney injury.

DOI: https://doi.org/10.1126/science.adp5384
bioRxiv. 2025 Jun 17. pii: 2025.06.16.659991. [Epub ahead of print]

Sustained Lysosomal Delivery of Enhanced Cy3-Labeled Acid Nanoparticles Restores Lysosomal pH in Retinal Pigment Epithelial Cells and Astrocytes.

Jiaqi Li, Tianchen Wang, Wennan Lu, Davit Jishkariani, Andrew Tsourkas, Simon Kaja, Rohini M Nair, Joshua L Dunaief, Claire H Mitchell.

Lysosomal pH is frequently elevated in age-dependent neurodegenerations like Age-related Macular Degeneration (AMD), Alzheimer's Disease (AD), and Parkinson's Disease (PD). Tools that restore lysosomal pH to an optimal acidic range could enhance enzymatic degradation and reduce waste accumulation. Acidic nanoparticles offer a promising strategy for restoring lysosomal function, but accurate tracking of organelle delivery and long-term retention is needed to optimize dosage. To improve detection and enhance delivery, nanoparticles were synthesized from Poly(D,L-lactide-co-glycolide) (PLGA) polymers covalently linked to the fluorescent Cyanine3 amine (Cy3) probe. Nanoparticle concentration and loading times were optimized to achieve >90% delivery to lysosomes in cultured induced pluripotent stem cell-derived retinal pigment epithelial (iPS-RPE) cells. Uptake was heterogeneous, varying between adjacent cells. Once loaded into lysosomes, the nanoparticles were stably retained, with no detectable changes in concentration, distribution, or size for at least 28 days. iPS-RPE cells internalized more nanoparticles than the ARPE-19 cell line or mouse optic nerve head astrocyte cultures. Functionally, PLGA nanoparticles restored an acidic pH and cathepsin D levels in compromised lysosomes. In summary, Cy3-PLGA nanoparticles enabled improved tracking and long-term delivery to lysosomes, supporting future in vivo applications to restore lysosomal pH in aging and degenerating tissues.
New and Noteworthy: Tools that restore acidic pH in compromised lysosomes can enhance autophagy and waste degradation in degenerative disorders marked by excessive accumulation. Here, we describe the novel synthesis of lysosome-targeted nanoparticles composed of PLGA polymers covalently bound to Cy3 fluorescent dye. These Cy3-PLGA nanoparticles enabled improved tracking of lysosomal delivery and demonstrated sustained long-term retention within lysosomes, supporting their potential for future applications to restore lysosomal pH in aging and degenerating tissues.

DOI: https://doi.org/10.1101/2025.06.16.659991
Dev Cell. 2025 Jul 09. pii: S1534-5807(25)00402-2. [Epub ahead of print]

PIF4 controls autophagy during hypocotyl response to elevated ambient temperatures via ArpC5 in Arabidopsis.

Qing Pan, Liangfeng Luo, Jiajing Li, Jiejie Li.

  Increased hypocotyl elongation is a key adaptive response of plants to high ambient temperatures (HATs). However, the underlying molecular mechanisms remain to be elucidated. This study identifies the role of ArpC5, a subunit of the ACTIN-RELATED PROTEIN 2/3(Arp2/3) complex, in Arabidopsis hypocotyl response to HAT. We demonstrate that PIF4 induces ArpC5 expression upon HAT exposure to regulate autophagy. ArpC5 promotes the assembly of actin cables essential for autophagosome formation. Additionally, ArpC5 interacts with ATG8 to facilitate autophagosome association and movement along actin cables under HAT conditions. Activated autophagy is required for the degradation of the auxin transporter and regulates polar auxin transport to drive hypocotyl cell elongation in response to HAT. Collectively, these findings elucidate the PHYTOCHROME-INTERACTING FACTOR 4 (PIF4)-Arp2/3 complex-actin cytoskeleton-autophagy axis and underscore its role in plant growth adaptation to elevated temperatures.

Keywords:  PIF4; actin cytoskeleton; autophagy; high ambient temperatures; hypocotyl elongation; the Arp2/3 complex; thermomorphogenesis

DOI:  https://doi.org/10.1016/j.devcel.2025.06.024
Trends Cell Biol. 2025 Jul 10. pii: S0962-8924(25)00127-8. [Epub ahead of print]

Proteoglycans are protagonists in autophagy, lymphangiogenesis, and neurodegenerative diseases.

Gabriel J Pascal, Sadie Kim, Christopher Xie, Dipon Mondal, Renato V Iozzo.

  Proteoglycans (PGs) are specialized cell-surface and secreted proteins teeming with bioactivity. They have been the subject of fascinating research on autophagy, lymphangiogenesis, and neurodegenerative diseases. PG influence on autophagy extends to several disease domains, and their ability to alter autophagic processes has highlighted their suitability as therapeutic targets. PGs also display new functions by evoking protracted autophagy in lymphatic endothelial cells and inhibiting tumor and physiological lymphangiogenesis. The variable degree of PG sulfation and their ability to regulate growth-factor activities in the central nervous system has opened doors into novel therapeutic avenues including Alzheimer's and Parkinson's diseases. This review systematically integrates these diverse qualities of PGs while highlighting future directions towards clinical application.

Keywords:  autophagy; lymphangiogenesis; neurodegeneration; proteoglycan; tau aggregation

DOI:  https://doi.org/10.1016/j.tcb.2025.06.002
Leuk Lymphoma. 2025 Jul 15. 1-11

BRMS1 suppresses the PI3K/AKT/mTOR pathway to regulate autophagy in multiple myeloma.

Nueramina Yimingniyazi, Maimaitiaili Abudureheman, Wulamujiang Aili, Nuerbiya Abudurexiti, Nueramina Rouzi, Aikebaier Abudureyimu, Ayimunisa Abudureheman.

  This study investigates the role of breast cancer metastasis suppressor 1 (BRMS1) in multiple myeloma (MM) progression. BRMS1 expression was significantly reduced in MM patient samples and cell lines. Functional assays revealed that BRMS1 overexpression suppressed MM cell proliferation, migration, and invasion while enhancing apoptosis and autophagic flux. Conversely, BRMS1 knockdown promoted tumorigenic behaviors. Pharmacological inhibition or activation of autophagy confirmed that BRMS1's tumor-suppressive effects are autophagy-dependent. Mechanistic studies demonstrated that BRMS1 regulates autophagy through the PI3K/AKT/mTOR signaling pathway. These findings establish BRMS1 as a potential tumor suppressor in MM, linking its function to autophagy and apoptosis regulation. Targeting BRMS1-mediated autophagy may provide a novel therapeutic approach for MM treatment and addressing disease progression. This study offers new insights into MM pathogenesis and potential strategies for improving patient outcomes.

Keywords:  BRMS1; Multiple myeloma; apoptosis; autophagy; tumor suppression

DOI:  https://doi.org/10.1080/10428194.2025.2531152
Int J Mol Sci. 2025 Jun 27. pii: 6210. [Epub ahead of print]26(13):

Ursolic Acid Suppresses Colorectal Cancer Through Autophagy-Lysosomal Degradation of β-Catenin.

Chung-Ming Lin, Min-Chih Chao, Hsin-Han Chen, Hui-Jye Chen.

  Colorectal cancer remains a leading malignancy. As the aberrant activation of Wnt/β-catenin signaling causes colorectal cancer, Wnt/β-catenin signaling inhibitors are potential candidates for colorectal cancer treatment. Our drug screening platform identified ursolic acid (UA), a triterpenoid with various biological activities, as a potential anticancer drug because it inhibits the T-cell factor (TCF)/β-catenin-mediated transcriptional activity. Here, we discovered that UA inhibited Wnt signaling by reducing the Wnt reporter activity and Wnt target gene expression, leading to a delay in cell cycle progression and the suppression of cell proliferation. Stepwise epistatic analyses suggested that UA functions on β-catenin protein stability in Wnt signaling. Further studies revealed that UA reduced β-catenin protein levels by Western blotting and immunofluorescent staining and induced autophagy by microtubule-associated protein 1 light chain 3 beta (LC3B) punctate staining. The cotreatment with UA and the autophagy inhibitors chloroquine and wortmannin recovered the β-catenin protein levels. Therefore, UA was confirmed to induce β-catenin degradation by the autophagy-lysosomal degradation system through inhibition in the phosphatidylinositol 3-kinase (PI3K)/Ak strain transforming (protein kinase B; AKT)/mammalian target of rapamycin (mTOR) signaling pathway. Our results not only highlight the potential of UA in Wnt-driven colorectal cancer therapy but also provide a workable Wnt signaling termination approach for the treatment of other Wnt-related diseases.

Keywords:  Wnt signaling; autophagy; colorectal cancer; ursolic acid; β-catenin

DOI:  https://doi.org/10.3390/ijms26136210
bioRxiv. 2025 Jun 25. pii: 2025.06.24.661349. [Epub ahead of print]

Lysosomal Enhancement Prevents Infection with PrP Sc , α-Synuclein & Tau Prions.

Robert C C Mercer, Nhat Tt Le, Nadia Mirza-Romero, Erin Flaherty, Giada Lavigna, Isabel C Orbe, Jean R P Gatdula, Douglas G Fraser, Aravind Sundaravadivelu, Janelle S Vultaggio, Aaron B Beeler, Roberto Chiesa, Glenn C Telling, David A Harris.

Prion diseases are fatal neurodegenerative diseases of humans and other mammals with no current treatment options. Here, we describe the characterization of a novel anti-prion compound, elacridar (GW120918), which has sub-micromolar activity in assays of prion infection, propagation and toxicity. Elacridar acts at an early step in the prion infection process, enhancing degradation of newly formed PrP Sc . The lysosome is the likely site of elacridars anti-prion effects, based on transcriptomic analysis and the use of functional lysosomal probes. Elacridar alters gene expression networks controlling lysosomal sterol and lipid metabolism but, unlike other lysosomotropic drugs, it prominently upregulates genes that control lysosomal pH. Surprisingly, these effects occur independently of TFEB nuclear translocation, suggesting novel regulatory mechanisms. The anti-prion effects of elacridar extend to α-synuclein and tau prions, highlighting lysosomal enhancement as a general strategy for the treatment of protein misfolding neurodegenerative diseases.

DOI: https://doi.org/10.1101/2025.06.24.661349