bims-auttor 2026-09-13 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–09–13
27 papers selected by
Viktor Korolchuk, Newcastle University

Deubiquitinases in mitophagy: therapeutic control of mitochondrial quality.
Canonical lymphocyte chemokine receptors CXCR3 and CXCR5 modulate neuronal autophagy.
"S-Tau-Lled" Lysosomes Disrupt Autophagic Processes in Neurodegeneration.
Spatiotemporal control of Atg9 vesicle fusion in autophagosome formation.
Augmenting intracellular amino acid pools suppresses the phenotypes of autophagy-deficient cells.
Glutaminase contributes to MYC-induced cell-autonomous autophagy and to Ras V12 -dependent non-autonomous autophagy in the Drosophila wing disc epithelium.
Insights Into the Mechanisms of Biological Aging That Guide Translational and Clinical Research.
Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size.
Retromer-targeted therapy for neurodegenerative diseases.
Proteostasis in the regulation of pancreatic islet cell plasticity.
The Secretome Derived From Human Umbilical Cord Mesenchymal Stem Cells Improves Skin Photoaging by Enhancing Mitophagy to Inhibit the cGAS-STING Pathway.
Autophagy in tuberculosis: advances, translational gaps, and the promise of host-directed therapies.
D-Amino Acid Prodrug DLMEH Activates mTORC1 via Sestrin2 to Restore Muscle Protein Synthesis in Sarcopenia.
GENETIC AND PHARMACOLOGIC ACTIVATION OF BECLIN1 PREVENTSALDOSTERONE-INDUCED CARDIOVASCULAR DAMAGE.
LAPTM5 correlates with RPE senescence and subretinal fibrosis through the LAPTM5-WWP2-OPTN mitophagy cascade and cGAS/STING activation in a D-galactose-induced aging model.
Knockdown of CDC20 attenuates pulmonary fibrosis by repressing fibroblast activation via the TSC1-mediated mTOR pathway.
Nerve injury-induced protein 2 preserves lysosomal membrane integrity to suppress ferroptosis.
AMBRA1 allosterically activates NLRP3 by releasing its autoinhibition.
The evolution of asymmetrical regulation of physiology is central to aging.
TRIM23 prevents adenovirus replication by p62-mediated selective autophagic degradation of viral E1A protein.
Targeting USP7 lactylation suppresses NSCLC tumorigenesis by promoting PINK1 ubiquitination and degradation.
TM184C is a GPCR-like regulator of intercellular exchange and autophagy.
The pan-AMPK activator MK-8722 outperforms the AMPK activators SC4 and A-769662 in human endothelial cells.
Discovering host-viral protein interactions in autophagy: A LIR discovery pipeline for identifying LC3-interacting region motifs in highly virulent viruses.
USP26 Promotes Autophagosome-Lysosome Fusion to Improve Mitochondrial Function in the Repair of Gut Barrier Damage by Stabilizing STX17.
Strengthening muscle for healthy ageing: innovative treatments for sarcopenia.
Targeted Lysosomal Degradation of Extracellular and Membrane Proteins: From Receptor Hijacking to Programmable Endolysosomal Routing.

Trends Pharmacol Sci. 2026 Sep 12. pii: S0165-6147(26)00206-3. [Epub ahead of print]

Deubiquitinases in mitophagy: therapeutic control of mitochondrial quality.

Yang Xu, Bahareh Behrouz, Andrew Lee, Gang Xin, Nuo Sun.

Mitochondrial quality control is essential for maintaining cellular and tissue homeostasis. Mitophagy, the selective autophagic removal of damaged mitochondria, is a central component of this process, and defects in mitophagy are increasingly linked to neurodegeneration, cardiovascular disease, cancer, and inherited mitochondrial disorders. Ubiquitin-dependent tagging of outer mitochondrial membrane proteins is a major mechanism for marking damaged mitochondria for clearance; however, recent advances reveal that mitochondrial deubiquitinases (DUBs) shape ubiquitin signaling at damaged mitochondria, thereby influencing the efficiency and selectivity of mitochondrial turnover. Moreover, DUBs are emerging as context-dependent editors of the mitochondrial ubiquitin code that link mitophagy to disease pathogenesis and therapeutic intervention. Here, we synthesize current understanding of mitochondrial DUBs in physiology and disease and discuss emerging pharmacological strategies to guide the development of mitophagy-targeted therapeutics.

DOI: https://doi.org/10.1016/j.tips.2026.08.009
Cell Death Differ. 2026 Sep 08.

Canonical lymphocyte chemokine receptors CXCR3 and CXCR5 modulate neuronal autophagy.

Matea Rob, Farah H Siddiqi, Junrui He, Yoshinori Tanaka, David C Rubinsztein.

Autophagy, a conserved cellular degradation process, plays a critical role in clearing toxic aggregate-prone proteins, which are characteristic pathological hallmarks of neurodegenerative diseases. As we previously found that microglia secreted factors impair neuronal autophagy and identified CCL3, CCL4 and CCL5 as causative chemokines, we screened the microglial secretome for soluble factors and neuronal cytokine receptors to identify candidates impacting autophagy in neuronal models. Against our expectations of identifying negative regulators, we found that two receptor-ligand pairs, CXCR3-CXCL10 and CXCR5-CXCL13, stimulated autophagy across several neuronal models, both in vitro (SH-SY5Y, i3Neurons) and in vivo. Mechanistically, CXCL10 and CXCL13 promoted autophagy through a shared mechanism: cognate receptor stimulation led to downstream activation of JNK, which in turn phosphorylates BCL-XL, promoting its disassociation from BECN1. The freed BECN1 interacts with VPS34 to form the autophagy initiation complex, enhancing autophagosome formation and flux. These findings reveal chemokine signalling as a targetable pathway for neuronal autophagy induction in neurodegeneration.

DOI: https://doi.org/10.1038/s41418-026-01865-9
Traffic. 2026 Sep;27(3): e70051

"S-Tau-Lled" Lysosomes Disrupt Autophagic Processes in Neurodegeneration.

Anaïs Bécot, Mehdi Kabani.

Tauopathies are a class of neurodegenerative diseases characterized by the accumulation of hyperphosphorylated, misfolded and aggregated Tau proteins and by dysfunctions in the autophagy-lysosome system. Whether the latter are a cause or a consequence of the former is unclear. The answer may come from a recent study by Mirfakhar et al. Using human iPSC-derived neurons harboring the MAPT p.R406W mutation in Tau, they were able to show that pathogenic Tau is able to broadly impair lysosomal function ahead of Tau accumulation. They also show that the degradative function of lysosomes, but not their motility, can be restored through pharmacological activation of autophagy, leading to reduced Tau levels. This work opens new therapeutic opportunities to eliminate early-on pathological misfolded Tau proteins before they can engage in a vicious cycle of aggregation, amplification and propagation.

DOI: https://doi.org/10.1111/tra.70051
Autophagy. 2026 Sep 09.

Spatiotemporal control of Atg9 vesicle fusion in autophagosome formation.

Takumi Kimura, Tetsuya Kotani, Hitoshi Nakatogawa.

  Atg9 vesicles serve as membrane seeds for autophagosome formation. These vesicles are derived from the Golgi/endosomes and localized to the pre-autophagosomal structure or phagophore assembly site (PAS) upon autophagy induction. How these vesicles are maintained as discrete membrane carriers while diffusing through the cytoplasm and subsequently become competent for downstream events at the PAS has remained unknown. Here, we show that the Atg9-interacting protein Atg23 remains associated with Atg9 vesicles following their formation and protects them from inappropriate fusion with endomembranes during their movement through the cytoplasm. Upon arrival at the PAS, Atg1-mediated phosphorylation of Atg9 triggers the dissociation of Atg23, thereby enabling efficient recruitment of the lipid-transfer protein Atg2. Collectively, these findings define a spatiotemporally regulated mechanism in which Atg23 preserves Atg9 vesicles during cytoplasmic transport, whereas its dissociation enables their productive utilization in autophagosome formation.

Keywords:  Atg9; Phosphorylation-dependent regulation; autophagosome; membrane trafficking; vesicle coating; yeast

DOI:  https://doi.org/10.1080/15548627.2026.2730073
Autophagy. 2026 Sep 07. 1-17

Augmenting intracellular amino acid pools suppresses the phenotypes of autophagy-deficient cells.

Rubén Barrios, Rebeca Gracia-Domingo, Cristina Corral-Ramos, Élida Alechaga, Óscar J Pozo, José Ayté, Elena Hidalgo.

  TORC1 is a central regulator of cell growth whose inactivation under conditions of nutrient deprivation triggers adaptive responses, including macroautophagy/autophagy, amino acid uptake, and sexual differentiation. Autophagy-deficient fission yeast cells display mating defects and are unable to recover from amino acid starvation, even when external amino acids are available. Here, we investigate how TORC1 signaling and autophagy interact to control these processes. We show that both major phenotypes of autophagy-deficient cells - their inability to resume growth after amino acid starvation and their mating defects - stem from insufficient intracellular amino acid pools. Genetic or environmental enhancement of intracellular amino acid pools alleviates both defects. During leucine starvation, deletion of any1 rescues the growth defect of atg1Δ mutants by maintaining amino acid transporters at the plasma membrane, promoting amino acid uptake. Importantly, we uncover a previously unrecognized role for autophagy in the cell-cycle remodeling required for sexual differentiation. Nitrogen depletion-mediated TORC1 inactivation initiates these cell-cycle rearrangements required to start the mating/meiosis program, but autophagy is specifically required for the final G2-to-G1 arrest that precedes the program. This step correlates with the accumulation of the cyclin-dependent kinase inhibitor Rum1. Metabolomic analyses reveal that intracellular amino acid pools drop sharply during nitrogen starvation, especially in autophagy-deficient cells, and supplementation with trace amino acids restores their ability to complete the final G2-to-G1 transition. Together, our results reveal that autophagy sustains intracellular amino acid pools during prolonged stress, enabling TORC1 reactivation and cell-cycle remodeling necessary for successful mating and meiosis.Abbreviations: DNA: deoxyribonucleic acid; FACS: fluorescence-activated cell sorting; GATOR1: GAP activity toward Rags 1; GATOR2: GAP activity toward Rags 2; GFP: green fluorescent protein; MM: minimal medium; N: nitrogen; PCR: polymerase chain reaction; RNA: ribonucleic acid; S. cerevisiae: Saccharomyces cerevisiae; S. pombe: Schizosaccharomyces pombe; TOR: target of rapamycin; TORC1: target of rapamycin complex 1; TORC2: target of rapamycin complex 2; tRNA: transfer ribonucleic acid; YE5S: yeast extract 5 amino acid supplemented; WT: wild-type.

Keywords:  Amino acid transporters; Eif21/eIf2α; Eliminate Gcn2; G1 arrest; Rum1; TORC1; leucine starvation

DOI:  https://doi.org/10.1080/15548627.2026.2719430
bioRxiv. 2026 Sep 02. pii: 2026.08.31.748041. [Epub ahead of print]

Glutaminase contributes to MYC-induced cell-autonomous autophagy and to Ras V12 -dependent non-autonomous autophagy in the Drosophila wing disc epithelium.

Francesca Destefanis, Lorenzo Conci, Shivani Bajaj, Valeria Manara, Paola Bellosta.

MYC-driven metabolic reprogramming supports rapid cell growth but also creates metabolic demands that require adaptive mechanisms to maintain cellular homeostasis. Here, combining clonal analysis in Drosophila wing imaginal discs with studies in Schneider S2 cells, we identify glutamine metabolism as a component of Myc-induced autophagy. Myc increased the expression of genes involved in glutamine utilization, including glutaminase (GLS), and enhanced ammonia production, a metabolic by-product of glutaminolysis. Genetic depletion of GLS in clones suppressed the accumulation of Myc-induced Atg8a-positive structures and reduced autophagic flux, demonstrating that glutaminase contributes to the autophagic response elicited by Myc. Exogenous NH₄Cl was sufficient to induce Atg8a-positive structures and partially restored their accumulation following GLS depletion, supporting ammonia as a downstream contributor to this response. Mechanistically, Myc-induced autophagy in clones required the core autophagy factor Atg5 but was not suppressed by activation of Rheb/TOR signaling or Atg1 depletion, indicating reduced dependence on canonical TOR-Atg1 regulation. We further found that Myc activity is required for Ras V12 -driven epithelial overgrowth and that Ras V12 cells induce a pronounced non-cell-autonomous accumulation of Atg8a-positive structures in wild-type cells surrounding Ras V12 clones. Depletion of either Myc or Gls in Ras V12 cells strongly reduced this neighboring autophagic response. Together, our findings identify Gls-dependent glutamine metabolism as a previously unrecognized component of Myc-induced autophagy and extend this relationship to Ras-transformed epithelia, linking the metabolic state of transformed cells to autophagy in the surrounding tissue.
Graphical abstract: Myc increases glutaminase (Gls)-dependent glutamine catabolism, promoting ammonia production and Atg5-dependent autophagy in Drosophila epithelial cells. In Ras V12- transformed epithelia, Myc and Gls are also required for the induction of autophagy in neighboring wild-type cells, suggesting that metabolic signals generated by transformed cells can elicit a non-cell-autonomous autophagic response. Solid arrows indicate experimentally supported relationships, whereas the dashed arrow denotes a proposed metabolic signal whose identity remains to be established.

DOI: https://doi.org/10.64898/2026.08.31.748041
Aging Med (Milton). 2026 Sep 05.

Insights Into the Mechanisms of Biological Aging That Guide Translational and Clinical Research.

Evandro Fei Fang, Hilde Nilsen, Morten Scheibye-Knudsen, Vilhelm A Bohr, Lin Kang.

  Understanding the molecular mechanisms of aging guides the development of prevention, intervention, and treatment strategies to reduce the incidence of common age-associated diseases. Over the past decades, the proposed key features (hallmarks) of aging cells have directly or indirectly provided us clues, furthering our understanding of the causes of disease and assisting with the development of therapeutic strategies for diseases such as rare premature aging diseases like Werner syndrome and ataxia telangiectasia (A-T), as well as the common age-related diseases like dementia and sarcopenia. In this editorial, we take a closer look at three of these hallmarks including genomic instability, defective macroautophagy, and mitochondrial dysfunction, and the applications of these concepts in understanding the progress of complex diseases. Mounting studies from the laboratory, supported by emerging clinical evidence, point to the reduction of the oxidized form of nicotinamide adenine dinucleotide (NAD+) as a commonality between many of these hallmarks of aging. Intriguingly, stimulating mitochondrial autophagy (mitophagy) via improvement of NAD+ availability appears to be a promising and effective therapeutic strategy for many diseases relating to aging. Future studies on the hallmarks of aging should address their internal linkages and clinical interventions.

Keywords:  DNA repair; NAD+; aging; autophagy; brain; mitophagy

DOI:  https://doi.org/10.1002/agm2.70107
JCI Insight. 2026 Sep 10. pii: e210523. [Epub ahead of print]

Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size.

Samuel C Lapp, Krystle C Kalafut, Madi Y Cissé, Khaled Tighanimine, Dean M Rosenthal, Will Doxsey, Sheng Hui, Karen E Inouye, Claire E Morrow, Yann Cormerais, Brendan D Manning.

  Activation of the mechanistic target of rapamycin (mTOR) complex1 (mTORC1) promotes muscle protein synthesis, mass, and function. Muscle mTORC1 can be activated by feeding and contraction. Here, muscle mTORC1 signaling, protein synthesis, mass, and function are characterized in a genetic mouse model that separates these two major modes of muscle mTORC1 regulation. AKT signaling is required for feeding-induced muscle mTORC1 signaling and protein synthesis, and mice expressing a mutant of tuberous sclerosis complex 2 (TSC2) that cannot be phosphorylated by AKT specifically in skeletal muscle (SkM-TSC2-5A) attenuate these effects of feeding. Despite this loss of postprandial protein synthesis, SkM-TSC2-5A mice have similar muscle and myofiber size compared to SkM-TSC2-WT mice. SkM-TSC2-5A mice maintain normal muscle mTORC1 activation in response to contraction and exhibit no differences in atrophy-related gene expression or ribosomal content. SkM-TSC2-5A mice exhibit improved maximal endurance capacity without changes in muscle contractile function. This phenotype occurs without alterations in muscle glycogen content or myofiber type but does coincide with a modest increase in muscle mitochondrial content. Therefore, AKT-mediated phosphorylation of TSC2 is required for postprandial mTORC1 activation and the induction of protein synthesis; however, these are dispensable for the development and maintenance of muscle mass in sedentary mice.

Keywords:  Endocrinology; Muscle biology; Signal transduction

DOI:  https://doi.org/10.1172/jci.insight.210523
Mol Neurodegener. 2026 Sep 10. pii: 55. [Epub ahead of print]21(1):

Retromer-targeted therapy for neurodegenerative diseases.

Michele Persico, Sophronea Tuithung, Alejandra Lorenzo, Darynaisha Crawford, Simona Eleuteri, David K Simon.

  Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are neurodegenerative diseases characterized by dysfunction of the endosomal-lysosomal system (ELS). Four shared neurodegenerative mechanisms across ALS, PD and AD are regulated by the ELS, namely proteostasis and related protein misfolding, mitochondrial function, neurotransmission and neuroinflammation. These mechanisms are interconnected, contributing to neurodegeneration in a "snowball" manner. The retromer, a multimeric, evolutionarily conserved protein complex involved in intracellular protein trafficking, is at the crossroad of these neurodegenerative processes. This narrative review focuses on exploring the retromer structure, function as a master regulator of the ELS, and how this impacts proteostasis, mitochondrial biogenesis and homeostasis, neurotransmission and neuroinflammation across neurodegenerative diseases. We explore how alterations in retromer function can play an important role in neurodegeneration and discuss the impact of genetic and pharmacological manipulations of VPS35, one of the main retromer subunits. In vitro and in vivo studies have identified that the retromer enhances the activity of protein degradation pathways via the ELS, namely macroautophagy, chaperone-mediated autophagy, and the ELS itself, with concomitant reduction in misfolded protein levels. Also, in some model systems, when the retromer role is enhanced or restored, mitochondrial function is rescued, dysfunctional neurotransmission is restored, and the damaging effects of neuroinflammation are dampened. Lastly, we highlight the role of a novel pharmacological class of agents that enhance retromer function as a strategy for potentially slowing the progression of these neurodegenerative diseases in in vivo models of PD and ALS. We discuss the challenges in targeting the retromer, current limitations and potential off-target effects of retromer enhancement. Overall, the retromer regulates shared mechanisms across neurodegenerative diseases and retromer enhancers could represent a novel disease-modifying strategy in AD, PD and ALS.

Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Neurodegeneration; Parkinson’s disease; Retromer; Therapy

DOI:  https://doi.org/10.1186/s13024-026-00971-z
J Diabetes Investig. 2026 Sep 11.

Proteostasis in the regulation of pancreatic islet cell plasticity.

Jun Shirakawa.

  Pancreatic islet cells continuously synthesize and secrete large quantities of peptide hormones, making them uniquely dependent on robust proteostasis networks to maintain cellular function. Traditionally, the unfolded protein response (UPR) is considered a stress-responsive pathway that protects cells from endoplasmic reticulum (ER) dysfunction or triggers apoptosis when ER stress is excessive. Here, we propose that proteostasis functions as an active physiological signaling network that governs islet cell adaptation, plasticity, and long-term homeostasis, extending beyond its conventional role in the response to cellular damage. In pancreatic β cells, glucose signaling suppresses the expression of the proapoptotic factor CHOP through both IRS2-dependent and IRS2-independent pathways, indicating that metabolic signaling directly remodels the ER stress response. In contrast, the CHOP-GADD34-eIF2α dephosphorylation axis constitutes a negative feedback mechanism that fine-tunes translational recovery and determines the balance between adaptation and cell death. Moreover, 4E-BP1-mediated inhibition of mRNA translation and modulation of mTOR signaling alleviate proteotoxic stress and promote β-cell survival under conditions of increased secretory demand. In addition to translational control, IGF2 receptor-mediated signaling has recently been implicated in the regulation of autophagy, further linking lysosomal quality control to β-cell proteostasis. Importantly, proteostasis also affects α-cell biology, where UPR signaling regulates glucagon secretion and contributes to α-to-β cell transdifferentiation, highlighting a previously unrecognized role of ER homeostasis in endocrine cell identity. Finally, recent findings indicate that progressive impairment of proteostasis is a hallmark of islet aging, integrating defects in protein folding, translation, autophagy, and stress adaptation into the pathogenesis of diabetes.

Keywords:  ER stress; alpha cell; beta cell; islet cell; proteostasis

DOI:  https://doi.org/10.1111/jdi.70438
Aging Cell. 2026 Sep;25(9): e70701

The Secretome Derived From Human Umbilical Cord Mesenchymal Stem Cells Improves Skin Photoaging by Enhancing Mitophagy to Inhibit the cGAS-STING Pathway.

Tingting Tang, Meifen Lin, Jingjing Yang, Xinyu Yang, Xunhong Xu, Xuan Wang, Yarui Zhang, Qimei Chen, Shan Zhao, Chenhui Guo, Hao Zhang, Min Zhang, Lin Zhang, Xueer Wang.

  Ultraviolet (UV)-induced skin photoaging is driven by cellular senescence and chronic inflammation. Although the secretome (SCT) derived from human umbilical cord mesenchymal stem cells (hUC-MSC SCT) exhibits regenerative potential, its role in combating photoaging remains to be elucidated. In this study, we show that SCT markedly ameliorates photoaging in UV-exposed mice, restoring epidermal barrier function, dermal collagen integrity, senescence-associated markers, and systemic inflammatory profiles. In UVB-irradiated human immortalized keratinocytes (HaCaT), SCT enhanced cellular viability, proliferation, and migration while alleviating cellular senescence. Mechanistically, SCT promoted mitophagy, as indicated by clearance of mitochondrial proteins (TOM20, TIM23, HSP60), reversal of p62 accumulation, and restoration of LC3B-II flux. By eliminating impaired mitochondria, SCT reduced cytosolic mtDNA leakage, thereby suppressing the overactivation of the cGAS-STING pathway and its downstream pro-inflammatory cytokines IL-6, IL-8, and IFN-β. Importantly, these protective effects were abolished by the mitophagy inhibitor Mdivi-1, whereas the STING inhibitor H151 effectively reversed the Mdivi-1-induced loss of protection, confirming that SCT acts through the hierarchical mitophagy-cGAS-STING axis. Together, our findings establish SCT as a promising cell-free therapeutic strategy for photoaging and highlight the mitophagy-cGAS-STING axis as a critical nexus linking mitochondrial quality control to sterile inflammation in aging tissues.

Keywords:  autophagy; cGAS‐STING; cell‐free therapy; mesenchymal stem cell; mitophagy; photoaging; secretome; skin inflammation

DOI:  https://doi.org/10.1111/acel.70701
Front Cell Infect Microbiol. 2026 ;16 1896798

Autophagy in tuberculosis: advances, translational gaps, and the promise of host-directed therapies.

Manjunath Challa, Jessy Padma B, Sivakumar Shanmugam.

  Tuberculosis (TB) is still a major global health threat, worsened by the advancement of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis (Mtb). Autophagy is a natural degradation and immune process that plays a critical role in the defence against intracellular pathogens, including Mtb. However, Mtb has developed complex mechanisms to evade autophagy by modulating phagosome-lysosome fusion, inhibiting xenophagy, and modifying host signaling pathways, including mTORC1 and AMPK, thereby suppressing epigenetically autophagy-related genes. These immune evasion strategies identify autophagy as a highly attractive target for host-directed therapies (HDTs). In many experimental models, several pharmacological and repurposed compounds, such as mTOR inhibitors, AMPK activators, lysosomal modulators, peptides, and small-molecule inhibitors, are promising factors in restoring autophagy, promoting bacterial clearance, and ameliorating inflammation. Despite the bright prospects of these preclinical studies, the intricacies of cellular pathways, the lack of selective autophagy modulators, the limited biomarkers, and the still inadequate models for translational research remain problematic. In this review, we summarise current insights into Mtb-mediated disruption of autophagy, evaluate emerging autophagy-enhancing HDTs, and highlight key biological and translational gaps. Further development of selective, system-level autophagy modulators may offer powerful adjunct therapies to improve TB treatment outcomes, especially in the era of escalating drug resistance.

Keywords:  Mycobaterium tuberculosis; TB treatment; autophagy; host-directed therapies; tuberculosis

DOI:  https://doi.org/10.3389/fcimb.2026.1896798
Mol Ther. 2026 Sep 11. pii: S1525-0016(26)00777-X. [Epub ahead of print]

D-Amino Acid Prodrug DLMEH Activates mTORC1 via Sestrin2 to Restore Muscle Protein Synthesis in Sarcopenia.

Jae Ho Shim, Ji Yeon Lee, Byung Kook Ahn, Sang Woo Woo, Jihye Han, Hyeon Soo Kim.

Sarcopenia, the age-related loss of skeletal muscle mass and function, lacks FDA-approved pharmacotherapy. The mechanistic target of rapamycin complex 1 (mTORC1), activated by leucine via Sestrin2, is the master regulator of muscle protein synthesis, but L-leucine suffers from rapid catabolism and poor bioavailability. Here, we report D-leucine methyl ester hydrochloride (DLMEH), a metabolically stabilized prodrug incorporating D-stereoisomer conversion, methyl esterification, and hydrochloride salt formation. Three orthogonal biophysical methods demonstrate that DLMEH directly binds Sestrin2 (Kd 28.3 μM), equivalent to L-leucine. Sestrin2 siRNA knockdown and rapamycin co-treatment confirm Sestrin2-dependent, mTORC1-specific activation. In human primary myotubes, DLMEH (100 μM) restores dexamethasone-suppressed protein synthesis by 58.2%, significantly exceeding L-leucine (800 μM, 28.5%). In a rat dexamethasone-induced atrophy model, intravenous DLMEH (100 mg/kg/day, 14 days) preserves gastrocnemius mass (19.3% rescue), grip strength (90% of normal), and treadmill endurance (85% of normal), all superior to oral L-leucine. RNA-seq reveals 41.7% reversal of dexamethasone-induced transcriptomic changes with enrichment in mTOR signaling, ribosome biogenesis, and oxidative phosphorylation. Safety profiling establishes NOAEL at 2000 mg/kg with therapeutic index greater than 30. DLMEH represents a first-in-class Sestrin2-targeting mTORC1 activator for sarcopenia.

DOI: https://doi.org/10.1016/j.ymthe.2026.09.007
Clin Sci (Lond). 2026 Sep 07. pii: CS20260969. [Epub ahead of print]

GENETIC AND PHARMACOLOGIC ACTIVATION OF BECLIN1 PREVENTSALDOSTERONE-INDUCED CARDIOVASCULAR DAMAGE.

Rafael M Costa, Ariane Bruder, Juliano V Alves, Debora M Cerqueira, Luis Oliveira de Moraes, Tyler Beling, Sergio Guerrero, Jacqueline Ho, Rita C Tostes, Thiago Bruder-Nascimento.

  Aldosterone promotes endothelial dysfunction and cardiovascular injury through mineralocorticoid receptor (MR) activation. Autophagy is essential for endothelial homeostasis, yet its role in aldosterone-mediated vascular dysfunction remains unclear. We tested whether aldosterone impairs autophagic flux and whether restoring autophagy via Beclin1 (BCN1) activation protects vascular and cardiac function. Endothelial and vascular responses to aldosterone were assessed in wild-type mice, BCN1 gain-of-function mice (Becn1), and mice treated with spermidine or a BCN1-activating TB-peptide. Vascular function, nitric oxide (NO)/reactive oxygen species (ROS) production, autophagy markers, endothelial migration, and cardiac fibrosis were evaluated using wire myography, fluorescence assays, Western blotting, confocal microscopy, migration assays, and histology. Aldosterone impaired endothelium-dependent relaxation, decreased NO, increased ROS, and impaired autophagic processing in an MR-dependent manner, as indicated by an increased LC3-II/LC3-I ratio, p62 accumulation, and reduced phosphorylated BCN1 expression. Spermidine restored endothelial function and normalized NO and ROS levels. BCN1 gain-of-function mice were protected from aldosterone-induced endothelial dysfunction and exhibited reduced coronary and myocardial fibrosis. TB-peptide activation of BCN1 enhanced autophagic flux, improved vascular function, decreased cardiac fibrosis, and rescued endothelial migration impaired by aldosterone. Aldosterone induces endothelial dysfunction by suppressing autophagic flux through MR activation. Genetic or pharmacologic enhancement of BCN1-dependent autophagy restores endothelial homeostasis and prevents vascular and cardiac injury, identifying autophagy activation as a promising therapeutic approach for cardiovascular diseases associated with mineralocorticoid excess.

Keywords:  oxidative stress; vascular biology; vascular function

DOI:  https://doi.org/10.1042/CS20260969
Geroscience. 2026 Sep 08.

LAPTM5 correlates with RPE senescence and subretinal fibrosis through the LAPTM5-WWP2-OPTN mitophagy cascade and cGAS/STING activation in a D-galactose-induced aging model.

Xiaowei Yang, Shenglai Zhang, Yan Wang, Jiarong Shi, Wenlong Li, Xueying Lou, Ying Yu, Jiangao Zhang, Aimin Sang.

  Retinal pigment epithelium (RPE) senescence acts as a core driver of subretinal fibrosis, a major irreversible pathological feature that exacerbates age-related macular degeneration (AMD). Mitophagy is essential for maintaining RPE homeostasis during aging. However, the upstream molecular mechanisms underlying mitophagy impairment in senescent RPE remain poorly defined. Here, we show that lysosomal-associated transmembrane protein 5 (LAPTM5) is significantly upregulated in human AMD specimens and D-galactose (D-gal)-induced aging mouse model, with its overexpression correlating with transcriptomic signatures of RPE senescence and fibrogenesis. Gain- and loss-of-function assays validate that LAPTM5 acts as an important regulator of RPE senescence and senescence-associated secretory phenotype (SASP) production. Mechanistically, LAPTM5 physically interacts with and promotes the lysosome-dependent degradation of WW domain-containing E3 ubiquitin protein ligase 2 (WWP2), which in turn diminishes optineurin (OPTN) polyubiquitination and ablates OPTN-mediated mitophagy. The resulting mitophagy deficiency is associated with cytoplasmic mitochondrial DNA leakage and sustained cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) innate immune activation, stimulating robust senescence-associated secretory phenotype (SASP) release that promotes RPE epithelial-mesenchymal transition (EMT) and exacerbates subretinal fibrotic scarring. Notably, AAV-mediated RPE-specific Laptm5 knockdown efficiently alleviates subretinal fibrotic lesions in the aged mouse model, while pharmacological STING inhibition with H-151 markedly attenuates EMT progression. Collectively, our findings identify a previously uncharacterized LAPTM5-WWP2-OPTN mitophagy cascade and reveal a new pathogenic circuit linking impaired mitophagy to RPE senescence and age-related retinal fibrosis, offering translational prospects for treating senescence-associated fibrotic diseases.

Keywords:  Age-related macular degeneration; LAPTM5; Mitophagy; Retinal pigment epithelium; Senescence-associated secretory phenotype; Subretinal fibrosis

DOI:  https://doi.org/10.1007/s11357-026-02506-2
Cell Signal. 2026 Sep 08. pii: S0898-6568(26)00545-0. [Epub ahead of print] 112886

Knockdown of CDC20 attenuates pulmonary fibrosis by repressing fibroblast activation via the TSC1-mediated mTOR pathway.

Yatao Guo, Mengchan Zhu, Ruyi Li, Jia Li, Jiming Si, Yuanhua Liu, Jingjing Mei, Yan Kang, Jianjun Jin.

  Idiopathic pulmonary fibrosis (IPF) is a fatal disease of the fibrous lungs that is closely associated with fibroblast activation. Cell division cycle protein 20 homolog (CDC20) regulates cell cycle progression, yet its role in lung fibrosis remains unclear. This study aimed to explore the function of CDC20 in IPF and investigate the potential mechanism of CDC20 to influence the progression of pulmonary fibrosis. Here, we found that the expression levels of CDC20 were upregulated in the lung tissue of mice with bleomycin (BLM)-induced pulmonary fibrosis, as well as in activated fibroblasts. Knockdown of CDC20 suppressed the activation of MRC-5 triggered by TGF-β1 via enhancing autophagy. Nevertheless, chloroquine (CQ)-mediated inhibition of autophagy abolished this regulatory effect on fibroblast activation. CDC20 knockdown also inhibited TGF-β1-induced migration and contraction of fibroblasts. CDC20 silencing had a protective effect against BLM-induced lung injury in mice, and CDC20 knockdown inhibited fibrosis in lung tissue and promoted autophagy. The interacting protein TSC1 with CDC20 was screened by IP/LC-MS, and Co-IP analysis showed that TSC1 interacted with CDC20, and CDC20 promoted the ubiquitination degradation of TSC1. Mechanistically, CDC20 boosted the ubiquitination and degradation of TSC1, and the reduction of TSC1 promoted the activation of the mTOR pathway to inhibit fibroblast autophagy, thereby facilitating fibroblast activation. Overall, CDC20 exacerbated pulmonary fibrosis by inhibiting fibroblast autophagy via blocking the mTOR signaling pathway, which suggested that targeting CDC20 might hold putative therapeutic effect in IPF.

Keywords:  Autophagy; CDC20; Fibroblast; IPF; TSC1; mTOR

DOI:  https://doi.org/10.1016/j.cellsig.2026.112886
Elife. 2026 Sep 11. pii: RP110919. [Epub ahead of print]15

Nerve injury-induced protein 2 preserves lysosomal membrane integrity to suppress ferroptosis.

Jin Zhang, Miranda Bustamante, Yang Shi, Ken-Ichi Nakajima, Xinbin Chen.

  Nerve injury-induced protein 1 (NINJ1), a cell adhesion molecule, is oligomerized during lytic cell death and mediates plasma membrane rupture to release large intracellular molecules that propagate the inflammatory response. We and others previously showed that NINJ2, a close relative of NINJ1, does not promote plasma membrane rupture to spread inflammation. Here, we identify that NINJ2 is necessary for lysosome membrane integrity to protect cells from ferroptosis. Specifically, we found that NINJ2 localizes to lysosomes and interacts with LAMP1, an anchor glycoprotein of the lysosome membranes and a sensor of stressed lysosomes. We also found that loss of NINJ2 exacerbates lysosomal membrane permeabilization (LMP), which allows for selective leakage of lysosomal contents, such as labile iron, into the cytosol. Accordingly, loss of NINJ2 elevates cellular labile iron accumulation and decreases expression of ferritins, the primary intracellular iron storage protein complexes. Mechanistically, we found that loss of NINJ2 promotes ferritin FTH degradation in lysosomes, which can be reversed by knockdown of LAMP1. Moreover, we found that loss of NINJ2 sensitizes cells to ferroptosis induced by RSL3 and Erastin, consistent with a recent study that loss of NINJ2 predisposes mice to chronic inflammation. Together, these findings uncover a previously unrecognized activity of NINJ2 from lysosome homeostasis to ferroptosis, which can be explored as a cancer therapeutic strategy, especially considering that NINJ2 and ferritins are found to be overexpressed and positively associated with iron-addicted cancers.

Keywords:  Lamp1; NINJ2; cancer biology; ferritin; ferroptosis; human; lysosomal membrane permeabilities

DOI:  https://doi.org/10.7554/eLife.110919
Nat Immunol. 2026 Sep 09.

AMBRA1 allosterically activates NLRP3 by releasing its autoinhibition.

Minghui Pan, Jie Zhou, Shuo Fu, Yuluan Tang, Gonglu Zou, Pilong Li, Zhengfan Jiang.

Nod-like receptor family pyrin domain-containing 3 (NLRP3) is activated by many stimuli, and its dysfunction is involved in various inflammatory diseases. Activation of NLRP3 is thought to happen via a multistep process involving phase separation, conformational opening and oligomerization. However, how NLRP3 is released from its autorepressed conformation remains elusive. Here we report that activating molecule in Beclin1-regulated autophagy protein 1 (AMBRA1), previously known for its role in autophagy, bound NLRP3 to scaffold and allosterically activate NLRP3. AMBRA1 engaged the leucine-rich repeat and helical domain 2 subdomains of NLRP3 through its β-propeller domain and destabilized the closed, inactive conformation of NLRP3, facilitating adenosine triphosphate binding and transition of NLRP3 to the active state. AMBRA1 deficiency in monocytes or macrophages impaired NLRP3 activation and reduced inflammatory responses in mouse models of endotoxic shock, colitis and sepsis. Nanobodies blocking the interaction between AMBRA1 and NLRP3 inhibited NLRP3 activation, underscoring the therapeutic potential of targeting this interaction. Our study revealed the role of AMBRA1 in NLRP3 inflammasome assembly and activation, offering potential pharmacological targets for related diseases.

DOI: https://doi.org/10.1038/s41590-026-02644-x
Ageing Res Rev. 2026 Sep 09. pii: S1568-1637(26)00360-0. [Epub ahead of print] 103368

The evolution of asymmetrical regulation of physiology is central to aging.

Mirre J P Simons, Marc Tatar.

  The evolutionary biology of aging is fundamental to understanding the mechanisms of aging and how to develop anti-aging treatments. Thus far most evolutionary theory concerns the genetics of aging with limited physiological integration. Here we present an intuitive evolutionary framework built on how physiology is regulated and how this regulation itself ages. Life has evolved to secure reproduction and avoid system failure in early life, and it is the regulation that evolves in response to those early life selection pressures that we suggest leads to the emergence of aging. The costs of dysregulation of physiology are not symmetrical, for example, they are not the same for over- and under-activation. As a consequence, asymmetry in the regulation of physiology will evolve. When asymmetrical regulatory systems break during aging, they cause physiological function to drift toward the physiological range where costs of dysregulation are lowest, rendering aging directional. Our model explains many puzzling aspects of the biology of aging. These include why aging appears (but is not) programmed, why aging is gradual yet heterogeneous, why cellular and hormonal signaling are closely related to aging, the compensation law of mortality, why trade-offs between reproduction and aging remain elusive, why longer-lived organisms show more signs of aging during their natural lifespans, and why longer-lived organisms can be less responsive to anti-aging treatments. We provide predictions of our theory that are empirically testable. By incorporating physiological regulation into evolutionary models of aging, we provide a novel perspective to guide research in this growing field.

Keywords:  Evolutionary Biology; Geroscience; mechanisms of aging; negative feedback; signaling

DOI:  https://doi.org/10.1016/j.arr.2026.103368
PLoS Pathog. 2026 Sep 08. 22(9): e1014578

TRIM23 prevents adenovirus replication by p62-mediated selective autophagic degradation of viral E1A protein.

Nan Sun, Jikai Zhang, Banruo Xia, Hang Yin, Jiaqian Xie, Xiaoxiao Liu, Man Li, Lin Fang, Guijuan Ji, Gaolei Ma, Haihan Zhang, Zhenzhen Wang, Dafei Chai, Gang Wang.

The E3 ubiquitin ligase TRIM23 is involved in diverse cellular processes, however, its function in antiviral defense against adenovirus remains unclear. Here, we identify a novel mechanism by which TRIM23 restricts human adenovirus type 5 (HAdV-C5) replication. TRIM23 expression was upregulated upon HAdV-C5 infection, and functional studies showed that its overexpression inhibited viral replication, while knockdown enhanced it. Mechanistically, TRIM23 interacts with the viral E1A protein and promotes its degradation through a mechanism dependent of its canonical E3 ligase activity. Moreover, TRIM23 recruits the selective autophagy receptor p62 promotes E1A degradation in a E1A ubiquitination-independent manner. Our results unveil a novel host defense pathway-the TRIM23-E1A-p62 axis-that highlights the role of selective autophagy in antiviral immunity.

DOI: https://doi.org/10.1371/journal.ppat.1014578
Autophagy. 2026 Sep 09. 1-19

Targeting USP7 lactylation suppresses NSCLC tumorigenesis by promoting PINK1 ubiquitination and degradation.

Zhangjie Wang, Chaoyi Li, Ruiqiu Zhu, Minghao Duan, Zhenyu Kuang, Xin Li, Weifang Cui, Chaojun Duan, Chunfang Zhang.

  Lactylation is an emerging post-translational modification that is well established for its involvement in epigenetic regulation. However, its functional significance and regulatory mechanisms in non-small cell lung cancer (NSCLC) remain poorly understood. In this study, integrated proteomic and lactylomic analyses of clinical NSCLC specimens and matched adjacent normal tissues showed that USP7 (ubiquitin specific peptidase 7) was upregulated and USP7 K1084 lactylation was increased in NSCLC. Knockout of USP7 or inhibition of USP7 lactylation impaired cellular mitophagy, resulting in mitochondrial damage and attenuated NSCLC tumorigenicity. We identified CREBBP/CBP (CREB binding lysine acetyltransferase) as the key lactyltransferase responsible for USP7 K1084 lactylation. USP7 lactylation induced its localization to mitochondria and increased its interaction with PINK1 (PTEN induced kinase 1), promoting PINK1 deubiquitination and stabilization. Pharmacological inhibition of CREBBP reduced USP7 lactylation levels and promoted PINK1 ubiquitination and degradation, exerting antitumor effects in vitro and in vivo. Analysis of NSCLC clinical specimens showed that the protein levels of USP7, CREBBP, and PINK1 were positively correlated, and their high expression was associated with poor patient prognosis. Collectively, our findings establish the CREBBP-USP7-PINK1 axis as a promising therapeutic target for NSCLC treatment.Abbreviations: CHX: cycloheximide; CREBBP/CBP: CREB binding lysine acetyltransferase; DUB: deubiquitinating enzyme; IHC: immunohistochemistry; IP: immunoprecipitation; KO: knockout; LDHA: lactate dehydrogenase A; MS: mass spectrometry; NALA: L-sodium lactate; NSCLC: non-small cell lung cancer; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PINK1: PTEN induced kinase 1; PLA: proximity ligation assay; ROS: reactive oxygen species; shRNA: short hairpin RNA; TEM: transmission electron microscopy; TUBE: tandem ubiquitin binding entity; UPS: ubiquitin-proteasome system; USP7: ubiquitin specific peptidase 7; WT: wild type.

Keywords:  CREBBP; deubiquitination; lung cancer; mitochondrial quality control; post-translational modification

DOI:  https://doi.org/10.1080/15548627.2026.2728617
Nature. 2026 Sep 09.

TM184C is a GPCR-like regulator of intercellular exchange and autophagy.

Kyutae D Lee, Samuel Taylor, Jennifer Arcuri, Shraddha Chandthakuri, Jacinda Pujols, Bruno Colon, Qiang Wang, Chenzhou Wu, Zhipeng Meng, Sebastian J Thompson-Ceccato, Jonathan Mitchell, Defne Bayik, Alexandra Carbone, Vladlen Slepak, Tatiana I Slepak, Scott M Welford, Michael E Ivan, Dazhi Wang, Blake O Goldberg, Warner Baringer, Elvis Maradzike, Daniel G Isom.

Sequence similarity underlies most protein annotation, yet many functions remain hidden beyond detectable homology1-3. By mining millions of AlphaFold2 models4,5, we identify two human families of 'superdark' seven-transmembrane proteins-TM184 and PRRT-with structural homology to G-protein-coupled receptors (GPCRs). These proteins exhibit hallmark GPCR activities, including β-arrestin recruitment and GPCR kinase (GRK)-dependent phosphorylation. Here we focus on TM184C-the most broadly expressed and evolutionarily conserved superdark GPCR-like protein, which localizes to highly dynamic intracellular vesicles rather than the plasma membrane. These vesicles move along microtubules, accumulate in cell projections and promote the formation of tunnelling nanotube- and tumour microtubule-like intercellular connections. These bridges mediate organelle sharing through a process that requires the TM184C C-terminal tail and its arrestin code motif6, linking GPCR-like β-arrestin and GRK regulation to vesicle function and intercellular connectivity. TM184C also constrains autophagic flux by limiting LC3B lipidation and autophagosome accumulation-a role that is deeply conserved, as human TM184C restores autophagic body homeostasis in yeast lacking its homologue, Hfl1. Together, these findings illustrate how structure-based protein discovery can illuminate the dark proteome and identify TM184C as an ancient GPCR-like regulator of autophagy, intercellular connectivity and material exchange.

DOI: https://doi.org/10.1038/s41586-026-10993-8
Biosci Rep. 2026 Sep 08. pii: BSR20250408. [Epub ahead of print]

The pan-AMPK activator MK-8722 outperforms the AMPK activators SC4 and A-769662 in human endothelial cells.

Heena Doshi, Katrin Spengler, Kanstantsin Siniuk, Marco Groth, Estelle Heyne, Michael Schwarzer, Amod Godbole, Yi Sing Gee, Jonathan Baell, Jonathan S Oakhill, Andreas Henke, Regine Heller.

  AMP-activated protein kinase (AMPK), a heterotrimeric serine/threonine protein kinase consisting of the catalytic α-subunit and regulatory β- and γ-subunits, regulates endothelial homeostasis. Consequently, it has emerged as a target for pharmacological activators in the treatment of endothelial dysfunction. However, the efficiency of these agonists may differ depending on the expression of different AMPK subunit isoforms in different cells and tissues, as these isoforms may form AMPK complexes with distinct activation profiles. This study compares the effects of three direct AMPK activators in endothelial cells: MK-8722, a pan-AMPK activator, SC4, an intermediate activator with preference for AMPKα2, and A-769662, a β1-specific compound. We demonstrate that MK-8722 (0.1 µM to 10 µM) induces a robust and sustained, short- and long-term activation of AMPK as evidenced by the phosphorylation of acetyl-CoA carboxylase (ACC) and the inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. On an equimolar basis, MK-8722 was significantly more potent than SC4 and A-769662. This was associated with a significant antiviral effect of MK-8722 against herpes simplex virus type 1 (HSV-1), whereas SC4 and A-769662 had no effect. At 10 µM, MK-8722 led to energy depletion and increased formation of mitochondrial and cytosolic reactive oxygen species (ROS) due to inhibition of mitochondrial complex I. Under these conditions, LKB1-mediated AMPK activation was observed but was not functionally relevant. We propose that the strong activation of AMPK by MK-8722 is related to the presence of different AMPK heterotrimers in endothelial cells. Therefore, targeting endothelial dysfunction pharmacologically may require pan-AMPK activators.

Keywords:  A-769662; AMPK; AMPK activators; Endothelial cells; MK-8722; SC4

DOI:  https://doi.org/10.1042/BSR20250408
PLoS Pathog. 2026 Sep 11. 22(9): e1014607

Discovering host-viral protein interactions in autophagy: A LIR discovery pipeline for identifying LC3-interacting region motifs in highly virulent viruses.

Kaylee D Petraccione, Haytham M Wahba, Mohamed G H Ali, Timothy Stocker, Ivan Akhrymuk, Yossira Swese, Danuta Sastre, Andrew Silberfarb, Paul E O'Maille, James G Omichinski, Kylene Kehn-Hall.

Hemorrhagic fever virus (HFV) infections are highly fatal, posing a significant global pandemic threat as they continue to emerge in new locations. HFVs and other highly virulent viruses (HVVs), such as Nipah virus, exploit host cell pathways, including the conserved host autophagy pathway, to promote viral replication. The Atg8/microtubule-associated protein 1 light chain 3 (LC3) proteins are necessary for autophagosome formation and maturation. Proteins interact with Atg8-family proteins through LC3-interacting region (LIR) motifs, which is a short linear motif (SLiM) found in intrinsically disordered regions of proteins. The presence of these motifs in viral components suggests they play a role in hijacking or evading the host autophagy pathway, yet the identification of functional LIR motifs in viral proteins remains limited. To address this gap, we developed the LIR Discovery Pipeline (LIR-DP) which integrates amino acid sequence pattern matching, with protein disorder prediction using IUPred3, and modeling with AlphaFold3. Using LIR-DP, we identified 43 putative LIR motifs in 166 proteins from 22 HVVs and predicted that 18 of these LIRs would be functional. In vitro and in cellulo laboratory experiments demonstrated that LIRs from the Marburg virus nucleoprotein, the Nipah virus phosphoprotein, the Ebola virus VP35, and the Rift Valley fever virus NSs protein bind to Atg8/LC3 family proteins. The aromatic amino acid in the first position of each LIR motif was found to be critical for these interactions. We provide evidence for the utility of the LIR-DP in identifying functional LIRs within HVV proteins which may provide valuable insight into the mechanism by which HVVs modulate the autophagy pathway during infection.

DOI: https://doi.org/10.1371/journal.ppat.1014607
Antioxid Redox Signal. 2026 Sep 07. 15230864261484565

USP26 Promotes Autophagosome-Lysosome Fusion to Improve Mitochondrial Function in the Repair of Gut Barrier Damage by Stabilizing STX17.

Weiming Li, Qinghua Zou, Jiaping Wang, Lili Ding, Hua Yang, Yijun Li, Qingwen Xu, Wenliang Li.

   AIMS: Intestinal mucosal barrier injury is a major consequence of intestinal ischemia-reperfusion (II/R) and contributes to poor clinical outcomes. While mitophagy sustains mitochondrial homeostasis, how impaired autophagic flux disrupts intestinal barrier function remains unclear. We investigated the role of the deubiquitinase ubiquitin-specific protease 26 (USP26) and its downstream target syntaxin 17 (STX17) in regulating mitophagy and intestinal barrier repair.
METHODS: II/R mouse models and oxygen-glucose deprivation/reperfusion (OGD/R)-treated Caco-2 cells were used to evaluate intestinal barrier integrity. Functional manipulation, autophagy blockade, Co-IP, ubiquitination assays, Seahorse metabolic detection, and in vivo rescue assays were performed to dissect the USP26-STX17 regulatory axis.
RESULTS: USP26 was markedly downregulated in II/R intestinal tissues and OGD/R Caco-2 cells, coinciding with impaired autophagy, mitochondrial dysfunction, and intestinal barrier disruption. USP26 overexpression preserved intestinal architecture, reduced permeability and apoptosis, and restored expression of the tight-junction proteins. Functionally, USP26 enhanced autophagic flux and mitophagy, as evidenced by increased LC3-II/LC3-I ratios, reduced p62 accumulation, elevated PINK1/Parkin signaling, improved adenosine triphosphate production, restored mitochondrial membrane potential, and normalized cellular bioenergetics; autophagy inhibition attenuated these protective phenotypes. Mechanistically, USP26 bound STX17 and stabilized it via deubiquitination. STX17 knockdown impaired autophagosome-lysosome fusion and largely abolished USP26-mediated mitochondrial and intestinal barrier protection in vitro and in vivo.
CONCLUSIONS: This study identifies the USP26-STX17 axis as a previously unrecognized regulator of autophagosome-lysosome fusion and mitophagy in II/R injury. By restoring mitochondrial quality control and epithelial barrier integrity, USP26 emerges as a promising therapeutic target for the prevention and treatment of gut barrier dysfunction associated with critical illness. Antioxid. Redox Signal. 00, 000-000.

Keywords:  STX17; USP26; autophagosome–lysosome fusion; intestinal mucosal barrier damage; mitochondrial function

DOI:  https://doi.org/10.1177/15230864261484565
Nat Rev Drug Discov. 2026 Sep 07.

Strengthening muscle for healthy ageing: innovative treatments for sarcopenia.

Sara Ancel, Emmeran Le Moal, Yu Xin Wang, Helen M Blau.

Millions of people worldwide suffer from sarcopenia, a clinically recognized syndrome that is defined as the age-related loss of skeletal muscle mass and strength. Sarcopenia reduces mobility, leads to falls and fractures, and increases the risk of death, posing an ever-increasing health-care and economic burden to society. There are currently no approved therapies for the syndrome, partly owing to its multifactorial aetiology, highlighting the need for therapies with pleiotropic beneficial effects on muscle function. Increased understanding of the cellular, metabolic and molecular mechanisms that drive muscle wasting with ageing is informing pharmacological interventions to increase muscle strength by promoting mitochondrial function (NAD+-related molecules, urolithin A), restoring impaired autophagy (mTORC1 inhibitors), promoting anabolic signalling (myostatin inhibitors), acting as selective androgen receptor modulators, maintaining vascularization (VEGF, apelin), reducing inflammageing (inhibitors of cytokine signalling), and restoring innervation, anabolism and regeneration (inhibitors of the gerozyme 15-PGDH). The recent surge in clinical trials combining weight loss-inducing GLP1RA therapies with drugs that preserve muscle tissue suggests that treatments that promote both healthspan and lifespan, or 'healthy ageing', are on the horizon.

DOI: https://doi.org/10.1038/s41573-026-01514-3
Adv Sci (Weinh). 2026 Sep 08. e77675

Targeted Lysosomal Degradation of Extracellular and Membrane Proteins: From Receptor Hijacking to Programmable Endolysosomal Routing.

Ke Liu, Xiyan Wang, Xiaozhen Liu, Chaoqi He, Da Qian, Xuli Meng, Liquan Zhu.

  Lysosome-targeting chimeras (LYTACs) have emerged as a strategy for eliminating secreted, extracellular, and plasma-membrane proteins by redirecting them to the endolysosomal system. By coupling target recognition to receptor-mediated uptake, LYTACs exploit endogenous trafficking pathways to access disease-associated proteins beyond the reach of conventional intracellular degradation mechanisms. Related target-intrinsic and cross-linking-driven strategies can likewise promote lysosomal target delivery without recruiting a separate clearance receptor. However, target internalization alone does not establish productive degradation. Following entry, target-containing complexes encounter a competitive endosomal network in which they may recycle, undergo retrograde transport or transcytosis, remain in non-degradative compartments, or proceed to lysosomes. Here, we present a routing-centered framework for understanding and designing extracellular and membrane-protein degradation. We discuss how target biology, receptor choice, tissue distribution, ligand competition, signaling liability, molecular architecture, and intracellular sorting shape degrader performance. We also outline evidence standards for distinguishing bona fide lysosome-dependent target loss from surface depletion, redistribution, epitope masking, shedding, secretion blockade, transcriptional effects, and nonspecific toxicity. Together, these principles define the transition from receptor hijacking to programmable endolysosomal routing.

Keywords:  Internalization; axoplasmic transport; cell biology; endocytic cycle; extracellular; membrane protein; protein degradation; transport protein; vesicle

DOI:  https://doi.org/10.1002/advs.77675