bims-auttor 2026-07-12 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–07–12
thirty-two papers selected by
Viktor Korolchuk, Newcastle University

Autophagy in the liver.
Molecular mechanisms of autophagy disorder in diabetic neuropathy: Focusing on signaling pathways and regulation of lipid metabolism.
OPTN (optineurin)-mediated selective substrate recognition in Golgi membrane-associated degradation.
Zinc-mediated lysosomal activation by 1H10 enhances autophagy and attenuates tau pathology in Alzheimer's disease models.
NSUN2 integrates glucose and one‑carbon metabolism upstream of Rag GTPase-dependent mTORC1 signaling.
TRIM21 induces selective autophagy of viruses and bacteria.
Mechanisms of autophagy-lysosome pathway impairment in Alzheimer's disease.
Rethinking PINK1/Parkin-mediated mitophagy in Parkinson's disease: functional continuity and activation-clearance uncoupling.
Autophagy in Alzheimer's disease: mechanisms, clinical trials, and horizons.
Nuclear Factor Y controls nutrient-adaptive epithelial growth by regulating mTOR in the Drosophila midgut.
Targeting Autophagy in Alzheimer's Disease: Role of the AMPK/mTOR Pathway and Drug Repurposing.
Syntaxin 12 Sustains Endosomal-Lysosomal Homeostasis and Survival in Glioblastoma Stem-Like Cells.
ATG5 Engineers Stem Cell Plasticity to Regulate Functional Fitness During Development and Disease.
CAMKV is an ISG and facilitates the degradation of rabies virus phosphoprotein via SQSTM1-mediated selective autophagy.
SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.
NAD+ modulates REST isoform expression and its downstream mitophagy in Alzheimer's disease.
Inhibiting VDAC1 oligomerization attenuated cerebral ischemia-reperfusion injury by promoting mitophagy via reduced LONP1 interaction.
Targeting the SNAI1-LAMP3 axis to restore lysosomal function and alleviate autophagic flux impairment to delay retinal degeneration.
Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.
Targeting lysosomes with a novel chloroquine derivative induces irreversible lysosomal damage and disrupts autophagosome and lysosome assembly in cancer.
Mitophagy in Metabolic Dysfunction-Associated Fatty Liver Disease: Mechanisms, Regulatory Networks, and Therapeutic Perspectives.
Metabolic Kinases as Regulators of Inter-Organelle Communication in Aging and Age-Related Diseases.
Hypoxia-preconditioned dental pulp stem cells alleviate acetaminophen-induced liver failure via promoting MYC-HIF1A/HIF-1α-BNIP3-mediated mitophagy.
Stimulating proteasomal degradation in human proteinopathies.
Cell-Type-Specific Calibration of Mitochondrial Ubiquitination in Stem Cell Fate Decisions.
Curcumin Attenuates Cuproptosis via Activating Autophagy Through Inhibition of the AKT/mTOR/P70S6K-Signaling Pathway in Parkinson's Disease Models.
The autophagy-senescence-inflammasome axis: A novel triad in neurodegenerative diseases?
Autophagy in cancer - functional plasticity, therapeutic paradox, and the road to precision modulation: a comprehensive review.
Triptolide-induced hepatotoxicity is mediated by NLRP3-dependent pyroptosis and inhibited by mitophagy.
Targeting of CH25H to boost p62-dependent autophagic degradation of α-synuclein in cell and mouse models of Parkinson's disease.
The UFSP2-ODR4 complex spatially confines and dynamically controls UFM1 deconjugation to safeguard neuronal proteostasis.
Local autophagy impairment triggers brain-wide presynaptic remodeling and resilience.

Autophagy Rep. 2026 ;5(1): 2698350

Autophagy in the liver.

Elijah Burks, Jenna Copes, Kelly Nguyen, Albert Tawil-Brown, Shengmin Yan.

  The liver plays a dynamic role in maintaining whole-body homeostasis through its control of nutrient metabolism, detoxification, and immune regulation. Autophagy, a conserved lysosomal degradation pathway, is central to these functions, enabling hepatocytes to adapt to fluctuations in nutrient availability, hormonal signals, and cellular stress. Hepatic autophagy is tightly regulated by nutrient and energy-sensing pathways, including AMPK, mTOR, the coordinated actions of insulin and glucagon, and transcriptional regulators TFEB, FOXO proteins, PPAR isoforms, FXR, and NRF2. Epigenomic mechanisms, chromatin remodeling complexes, and post-transcriptional regulators, such as microRNAs (miRNAs), RNA-binding proteins (RBPs), and liquid-liquid phase separation (LLPS), further refine autophagy gene expression and autophagosome formation. In physiological conditions, autophagy maintains hepatocyte integrity by supporting lipid, carbohydrate, and protein turnover and by clearing damaged or excess organelles through selective pathways such as mitophagy, lipophagy, pexophagy, ER-phagy, and xenophagy. Autophagy dysfunction contributes to the development of various liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), cholestatic liver disease, liver fibrosis, and hepatocellular carcinoma (HCC). Understanding the diverse regulatory networks governing hepatic autophagy, along with the roles of autophagy in liver homeostasis, provides new opportunities for therapeutic intervention. This review summarizes existing findings on the role of autophagy in the liver, focusing on recent advances in the regulation of hepatic autophagy. It also highlights unresolved mechanisms and discusses how targeting autophagy may offer novel strategies for treating liver diseases.

Keywords:  Autophagy; liver disease; liver homeostasis; macroautophagy; metabolism

DOI:  https://doi.org/10.1080/27694127.2026.2698350
PLoS One. 2026 ;21(7): e0344082

Molecular mechanisms of autophagy disorder in diabetic neuropathy: Focusing on signaling pathways and regulation of lipid metabolism.

Li Song, Lin Zhou, Weiwei Li.

Diabetic neuropathy, a prevalent and debilitating complication of diabetes mellitus, is characterized by progressive neuronal dysfunction. This study investigates the role of autophagy dysregulation in the pathogenesis of diabetic neuropathy and explores potential therapeutic interventions. Using a combination of in vitro and in vivo models, we demonstrate that chronic hyperglycemia leads to impaired autophagic flux in neurons, evidenced by decreased LC3I/II ratio and increased p62 accumulation. This autophagy dysfunction is associated with alterations in key signaling pathways, including mTOR activation and AMPK inhibition. Transcriptomic analysis reveals dysregulation of autophagy-related transcription factors, notably TFEB, FOXO3, and NRF2. We identify a novel bidirectional relationship between autophagy impairment and lipid metabolism dysregulation, suggesting a potential vicious cycle contributing to neuronal dysfunction. These findings provide new insights into the molecular mechanisms underlying diabetic neuropathy and highlight promising avenues for therapeutic intervention, potentially leading to improved management strategies for this challenging complication.

DOI: https://doi.org/10.1371/journal.pone.0344082
Autophagy. 2026 Jul 08. 1-2

OPTN (optineurin)-mediated selective substrate recognition in Golgi membrane-associated degradation.

Yoichi Nibe-Shirakihara, Shigeomi Shimizu.

  Golgi membrane-associated degradation (GOMED) is a protein degradation pathway that primarily targets proteins transiting through the trans-Golgi cisternae, and functions constitutively or in response to abnormalities in Golgi-trafficked cargos. Although GOMED is morphologically similar to macroautophagy/autophagy, its substrate recognition mechanism has remained unclear to date. In this study, we identified OPTN (optineurin) as an essential receptor protein for selective cargo recognition in GOMED. We found that OPTN binds K33-linked polyubiquitinated proteins that have passed through the Golgi apparatus and delivers them to GOMED structures for degradation. In vivo, OPTN-dependent GOMED is required for mitochondrial clearance during erythrocyte maturation, and Optn-deficient mice have erythrocytes that retain mitochondria. Taken together, our findings define the molecular basis of selective cargo recognition in GOMED.

Keywords:  Golgi membrane-associated degradation (GOMED); K33-linked polyubiquitin; OPTN (optineurin); organelle quality control; selective GOMED

DOI:  https://doi.org/10.1080/15548627.2026.2698749
Mol Brain. 2026 Jul 08.

Zinc-mediated lysosomal activation by 1H10 enhances autophagy and attenuates tau pathology in Alzheimer's disease models.

Jae-Won Eom, Ki-Ryeong Kim, Dong-Hyuk Kim, Jae Gwang Song, Chaeeun Han, Hyung Wook Kim, Seoungjun Ha, Woon Ju Song, Yang-Hee Kim.

  Impaired autophagic flux and lysosomal dysfunction contribute critically to the accumulation of pathological protein aggregates in Alzheimer's disease (AD). Emerging evidence suggests that intracellular zinc dynamics regulate lysosomal function by modulating processes such as acidification and lysosomal biogenesis. We previously identified 1H10 as an AMP-activated protein kinase (AMPK) inhibitor and subsequently demonstrated its zinc-binding capacity and ability to regulate intracellular zinc homeostasis. Building on our prior findings that intra-lysosomal zinc promotes acidification and activates transcription factor EB (TFEB), we investigated whether 1H10 enhances lysosomal function through zinc mobilization in neurons, thereby improving autophagy and reducing pathological protein accumulation. In primary cortical neurons, 1H10 increased lysosomal abundance and enhanced lysosomal degradative capacity in a zinc-dependent manner, as demonstrated by increased cathepsin B activity and DQ-BSA degradation. It alleviated lysosomal dysfunction induced by v-ATPase inhibition and promoted autophagic flux, leading to reduced accumulation of amyloid-β (Aβ) and tau in neuronal models. In 5XFAD mice, 1H10 treatment showed trends toward improved spatial learning in the Morris water maze, reduced tau phosphorylation at Thr205 and Ser214, normalized LC3-II levels, and restored autophagic-lysosomal homeostasis, without significant changes in extracellular amyloid plaque burden. These findings indicate that zinc-mediated lysosomal activation by 1H10 enhances the autophagy-lysosomal pathway and attenuates tau pathology in AD models, suggesting that targeting lysosomal function may represent a potential therapeutic strategy for neurodegenerative disorders characterized by impaired proteostasis.

Keywords:  Alzheimer's disease; Autophagic flux; Lysosome; Tau; Zinc

DOI:  https://doi.org/10.1186/s13041-026-01328-9
Cell Signal. 2026 Jul 09. pii: S0898-6568(26)00391-8. [Epub ahead of print] 112734

NSUN2 integrates glucose and one‑carbon metabolism upstream of Rag GTPase-dependent mTORC1 signaling.

Xueyi Chen, Li Xiao, Yiying Zhou, Zeyu Wu, Xu Xu, Tao Qiu, Rui Chen.

  How glucose and one‑carbon metabolism converge on Rag GTPase-dependent mechanistic target of rapamycin complex 1 (mTORC1) remains poorly defined, particularly in the absence of AMP-activated protein kinase (AMPK). This study mapped an AMPK-independent glucose-response pathway in human cells using CRISPR editing, rescue assays, proteomics, thermal stability analysis, and RNA sequencing. In AMPK-deficient human cells, glucose refeeding rapidly reactivated mTORC1, and proteomics of mTORC1-associated complexes identified NSUN2 as a glucose-associated factor. NSUN2 loss markedly reduced glucose-induced mTORC1 activation, whereas re-expression restored it. Genetic analyses placed NSUN2 upstream of the lysosomal Rag module because constitutively active Rag GTPases bypassed NSUN2 deficiency. Structure-function studies showed that the acute signaling role of NSUN2 was largely independent of its catalytic cysteines, but required an N-terminal nutrient-responsive motif and a predicted S-adenosylmethionine (SAM)-responsive segment. SAM increased the thermal stability of wild-type NSUN2, and proteomics and Immunoprecipitation identified methionine adenosyltransferase 2 A (MAT2A), a SAM-producing enzyme, as a glucose-responsive NSUN2 partner. MAT2A knockout reproduced the signaling defect. Transcriptomics further linked NSUN2 to glucose-responsive programs in proteostasis, secretion, and stress adaptation. These results identify NSUN2 as a noncanonical signaling factor that couples glucose and methyl-donor availability to Rag-dependent mTORC1 control and transcriptional adaptation.

Keywords:  Glucose sensing; NSUN2; Nutrient signaling; Rag GTPases; S-adenosylmethionine; mTORC1

DOI:  https://doi.org/10.1016/j.cellsig.2026.112734
Autophagy. 2026 Jul 08.

TRIM21 induces selective autophagy of viruses and bacteria.

T Rhinesmith, A Albecka, L C James.

  Antibodies are known to prevent infection by binding to pathogens extracellularly and blocking their entry into cells. What is less well known is that a proportion of pathogens, called the persistent fraction, still succeed in entering cells despite the antibodies bound to their surface. Fortunately, all mammalian cells express a dedicated cytosolic antibody receptor called TRIM21 that intercepts these incoming antibody-bound pathogens as soon as they enter the cytosol. Once it has detected an infection event, TRIM21 uses its E3 ubiquitin ligase activity to target pathogens for degradation. Our early work showed that TRIM21-mediated neutralization was both a fast and efficient process, capable of causing the degradation of incoming viral particles within hours. What was less clear was how TRIM21 achieves this degradation. In a recent study, we reveal that TRIM21 mediates a system of selective autophagy to direct incoming pathogens into the lysosome.Abbreviations:TRIM21:Tripartite-motif containing protein 21; VCP: Valosin-Containing Protein. CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats; FACS: fluorescence activated cell sorting; GFP: green fluorescent protein; LC3: Microtubule-associated Protein 1 Light Chain 3; TBK1: TANK-binding kinase 1; FIP200: FAK family kinase-interacting protein of 200 kDa; ULK1: Unc-51-like autophagy activating kinase 1; PI3K: Phosphoinositide 3-Kinase; ATG: autophagy-related gene; TMEM41B: transmembrane protein 41B; VPS37A: Vacuolar Protein Sorting-Associated Protein 37A; RBSN: Rabenosyn-5; EPG5: Ectopic P-Granules 5 Autophagy Tethering Factor; NDP52: Nuclear Dot Protein 52; ADX: antibody-dependent xenophagy; p62/SQSTM1: Protein 62/ Sequestosome 1; LPS: Lipopolysaccharide.

Keywords:  Antibodies; TRIM21; bacteria; viruses; xenophagy

DOI:  https://doi.org/10.1080/15548627.2026.2701600
J Alzheimers Dis. 2026 Jul 10. 13872877261460879

Mechanisms of autophagy-lysosome pathway impairment in Alzheimer's disease.

Kun Lu, Yirui Lu, Runyu Tang, Xiaofeng Dong, Pingping Zhuang, Yu Gao, Min Cheng, Yi Wang, Yubing Wang.

  The autophagy-lysosomal pathway is key for the removal of harmful substances in cells. This article integrates evidence that highlights the role of lysosomal function and the autophagy-lysosomal pathway in maintaining intracellular homeostasis and the effects of their dysfunction on protein secretion and metabolic disorders, leading to the pathogenesis of Alzheimer's disease (AD) and other tau diseases. Dysfunction of the autophagy-lysosomal pathway is believed to be the main factor leading to the accumulation of amyloid-β and tau proteins, which are also pathological features of AD. This article also discusses why autophagy is indispensable in the early to mature stages of neuronal development and how damage to the function of autophagy can cause neurodevelopmental abnormalities and neurodegenerative diseases. We also summarized the potential role of oligodendrocytes. We believe that its relationship with lysosomes can provide a new perspective and research direction for future research on neurodegenerative diseases. Autophagy-lysosomal pathway damage is considered to be a key factor in the pathology and diagnosis of multiple sclerosis, but we believe that the challenge associated with its transformation into clinical treatment is enormous. These findings suggest that enhancing or improving autophagy function may be an effective treatment method to alleviate the condition of AD patients, which can provide new strategies for clinical treatment and intervention of AD in the future.

Keywords:  Alzheimer's disease; amyloid-β; autophagy; tau proteins

DOI:  https://doi.org/10.1177/13872877261460879
Front Aging Neurosci. 2026 ;18 1865383

Rethinking PINK1/Parkin-mediated mitophagy in Parkinson's disease: functional continuity and activation-clearance uncoupling.

Lingzhe Wang, Bin Xu.

  Mitochondrial dysfunction is a central feature of Parkinson's disease (PD) and contributes to the selective vulnerability of nigral dopaminergic (DA) neurons. Among the pathways that maintain mitochondrial integrity, PINK1/Parkin-mediated mitophagy has been extensively characterized as a stress-responsive mechanism for the recognition and removal of damaged mitochondria. However, despite robust activation of this pathway in experimental systems, translation of these findings into effective disease-modifying strategies has remained limited. Here, we propose that a conceptual distinction may help account for this gap. Current research has largely focused on pathway activation as a surrogate for functional recovery, yet mitochondrial quality control depends on the maintenance of functional continuity across multiple sequential steps, from damage recognition and ubiquitin signaling to autophagosome formation and lysosomal degradation. Disruption at any of these stages may compromise overall pathway output. Accumulating evidence suggests that, under PD-relevant conditions, upstream signaling and downstream mitochondrial clearance can become partially uncoupled, such that activation of the PINK1/Parkin pathway does not necessarily ensure effective completion of mitophagy. Within this framework, mitochondrial dysfunction interacts with α-synuclein (α-syn) accumulation, lysosomal impairment, and neuroinflammatory signaling to form a self-reinforcing pathological network. This perspective provides a mechanistic basis for understanding why strategies that enhance upstream signaling alone have shown limited translational success. Finally, we discuss key challenges for therapeutic development, including the need for readouts that distinguish pathway engagement from pathway completion, the limitations of current model systems, and the importance of aligning patient stratification and intervention timing with pathway biology. We suggest that restoring functional continuity across the mitophagic process, rather than focusing exclusively on increasing pathway activation, may offer a more productive conceptual basis for targeting mitochondrial dysfunction in PD.

Keywords:  PINK1; Parkin; Parkinson’s disease; functional uncoupling; lysosomal dysfunction; mitochondrial quality control; mitophagy; neuroinflammation

DOI:  https://doi.org/10.3389/fnagi.2026.1865383
Neurodegener Dis. 2026 Jul 09. 1-21

Autophagy in Alzheimer's disease: mechanisms, clinical trials, and horizons.

Tshibambe N Tshimbombu, Kyle E Thurmann, Boris Decourt, Arsene Daniel Nyalundja, Samira Braimah Shardow, Melissa Ewurakua Amoako, Gates Mulume Iragi, Josué Aganze Mwambali, Marwan N Sabbagh.

BACKGROUND: Alzheimer's disease (AD) is an incurable progressive neurodegenerative disorder characterized by the pathological accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles in the brain. Recent findings have identified dysregulation of autophagy, a cellular mechanism for degradation and recycling, as a crucial contributor to the pathogenesis of AD. This narrative review examines the role of autophagy in the metabolism of Aβ and tau and evaluates current therapeutic strategies aimed at modulating autophagic pathways.
SUMMARY: Autophagy is governed by the key molecular regulators mammalian target of rapamycin, adenosine monophosphate-activated protein kinase, Beclin-1, and transcription factor EB, which collectively control the clearance of protein recycling, including aggregates, inside cells. Pharmacological agents such as rapamycin, resveratrol, and trehalose, alongside sigma-1 receptor agonists and gene therapy approaches, have demonstrated potential in modulating autophagy in preclinical and clinical studies. Despite these advances, significant challenges persist; namely, neuronal heterogeneity, optimal timing for therapeutic intervention, and the absence of reliable biomarkers to monitor autophagic activity and treatment efficacy.
KEY MESSAGES: Targeting autophagy offers a promising and potentially safe avenue for slowing AD progression. Future investigations should prioritize the development of selective autophagy modulators and personalized treatment strategies to restore autophagic flux and enhance clinical outcomes in patients with AD.

DOI: https://doi.org/10.1159/000553506
Development. 2026 Jul 01. pii: dev205643. [Epub ahead of print]153(13):

Nuclear Factor Y controls nutrient-adaptive epithelial growth by regulating mTOR in the Drosophila midgut.

Tetiana Strutynska, Onur Deniz, Jaakko Mattila.

  The intestinal epithelial lining is highly dynamic, with size and cellular composition adapting to nutrient status. This requires regulation of intestinal stem cell (ISC) proliferation and enterocyte size. How the intestinal absorptive area matches physiological nutrient conditions remains unclear. Here, we show that the transcription factor Nuclear Factor Y (NF-Y) plays a role in this process. NF-Y loss of function in ISCs led to high proliferation and cell growth, a phenotype influenced by dietary nutrients. NF-Y loss of function also increased nutrient metabolism, as shown by more mitochondria and larger lipid droplets in progenitors. Mechanistically, NF-Y restrains mTOR complex 1 (mTORC1) activity in ISCs by controlling transcription of mTORC1 signaling components such as Pras40 and Sestrin. Overall, our results demonstrate that NF-Y limits excessive nutrient-adaptive intestinal epithelial growth.

Keywords:   Drosophila midgut; Intestinal stem cell; NF-Y; Tissue growth; mTOR

DOI:  https://doi.org/10.1242/dev.205643
Drug Dev Res. 2026 Aug;87(5): e70344

Targeting Autophagy in Alzheimer's Disease: Role of the AMPK/mTOR Pathway and Drug Repurposing.

Ayush Dubey, Ayush Chaurasia, Zeeshan Ansari, Santosh Kumar Kushwaha, Isha Saraf, Sushil Kashaw, Rajan Swami, Varun Kushwah.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques and tau (τ) -related neurofibrillary tangles, often exacerbated by dysfunctional cellular clearance mechanisms. This manuscript explores the pivotal role of autophagy impairment in AD pathogenesis, with a specific focus on the AMPK/mTOR signaling axis as a primary regulatory pathway. Findings revealed that while mTOR overactivation suppresses autophagic flux and promotes the buildup of toxic protein aggregates, the activation of AMPK serves to restore homeostatic degradation processes. The review highlights that various pharmacological agent including rapamycin, metformin, trehalose, and curcumin, as well as repurposed drugs like lithium and statins can effectively enhance autophagy to ameliorate cognitive decline and neuroinflammation. Furthermore, herbal formulations such as Danggui Shaoyao San and phytoconstituents like Icariin demonstrate significant neuroprotective potential by modulating these same molecular pathways. Targeting autophagy represents a translationally viable approach for combating AD progression, with drug repurposing offering a time-efficient and cost-effective strategy. To advance these findings, future research should prioritize large-scale clinical trials to validate the efficacy of autophagy-inducing agents in human subjects. Additionally, investigating synergistic combinations of traditional bioactives with synthetic drugs and utilizing innovative delivery systems, such as intranasal nanotechnology-based platforms to bypass the blood-brain barrier, represents a promising frontier for developing effective, multi-targeted treatments against AD.

Keywords:  Alzheimer; amyloid‐β; autophagy; drug repurposing; mTOR; neurodegeneration; τ protein

DOI:  https://doi.org/10.1002/ddr.70344
Traffic. 2026 Sep;27(3): e70042

Syntaxin 12 Sustains Endosomal-Lysosomal Homeostasis and Survival in Glioblastoma Stem-Like Cells.

Clément Maghe, Agnieszka Barbach, Gwennan André-Grégoire, Clotilde C N Renaud, Margaux Le Guyon, Rosalie Moreau, Nicolas Bidère, Julie Gavard.

  Glioblastoma cells display a striking vulnerability to disruptions in late endosome-lysosome trafficking, a dependency that we exploited through a targeted siRNA screen in patient-derived cells with stem-like properties (GSCs). This screen identified Syntaxin 12 (STX12) as a critical determinant of GSC survival. Originally characterized as a recycling endosome t-SNARE, STX12 regulates tubular recycling and retrograde transport, yet its broader implications for lysosomal homeostasis remain poorly understood. Functional characterization revealed that STX12 is required to maintain lysosomal organization in GSCs, consistent with its known roles as an endosomal t-SNARE. Loss of STX12 altered dynamic processes that support GSC fitness, culminating in controlling life-and-death decisions. Because lysosomal function is deeply connected with the autophagic pathway, we next explored whether STX12 contributes to this adaptive program. STX12 silencing produced signatures consistent with impaired endo-lysosomal progression and disrupted mechanistic target of rapamycin (mTOR)/lysosome communication. This work further identifies a previously unrecognized role for STX12 in the adaptive trafficking network that supports glioblastoma cell survival, revealing a potential SNARE-centered vulnerability for therapeutic intervention.

Keywords:  cell death; endo‐lysosome; glioblastoma; lysosomes; mTOR signaling; recycling; trafficking

DOI:  https://doi.org/10.1111/tra.70042
Stem Cells Dev. 2026 Jul 09. 15473287261463931

ATG5 Engineers Stem Cell Plasticity to Regulate Functional Fitness During Development and Disease.

Fahika Nazeerulla, Ishani Banerjee, Manash Kumar Paul, Subhadip Mukhopadhyay.

  Autophagy, an evolutionarily conserved and tightly controlled process in eukaryotic cells, allows them to respond to stress by selectively eliminating dysfunctional or unwanted materials to promote metabolic flexibility and maintain homeostasis. While autophagy is orchestrated by different autophagy (ATG)-related genes, whose regulation varies considerably according to tissue type and developmental stage. In this review, we investigate how regardless of the different players involved in autophagy, ATG5 emerges as a unique, highly conserved, critical molecule that acts as a central rheostat to control the stem cell fate, metabolic adaptability, and govern the immune signature pattern in cells. The journey of ATG5 modulation from physiological developmental variation to pathological scenario brings out the translational impact of ATG5. On the one hand, ATG5 promotes exit from the pluripotent state by c-Myc degradation during differentiation of specific lineages (involved in neurogenesis, adipogenesis, and hematopoiesis), while on the other hand, it has a critical involvement in metabolic circuitry via rewiring autophagy through modulation of lipophagy, mitophagy, and acetyl-CoA epigenetics. Taken together, this work summarizes new findings that centrally place ATG5 as a driver that engineers a coordinated crosstalk between the metabolic state and cell fate decisions and immune responses. These insights position ATG5 as a critical and therapeutic target for developmental disorders, cancer, and immune-metabolic diseases.

Keywords:  ATG5; autophagy; differentiation; immune signature; stem cell

DOI:  https://doi.org/10.1177/15473287261463931
Autophagy. 2026 Jul 05.

CAMKV is an ISG and facilitates the degradation of rabies virus phosphoprotein via SQSTM1-mediated selective autophagy.

Jinming Wang, Hong Huo, Yuting Tao, Jinliang Wang, Xijun Wang, Zhiyuan Wen, Jinying Ge, Weiye Chen, Zhigao Bu, Lei Shuai.

  Once rabies virus (RABV) gains access to the central nervous system, infection almost inevitably results in fatal outcomes, and our incomplete understanding of viral pathogenesis remains a major barrier to effective therapeutic intervention. Here, we identify CAMKV as an interferon-stimulated gene (ISG) that drives the macroautophagic/autophagic degradation of RABV phosphoprotein (P), thereby potently suppressing viral replication in vitro. Notably, in vivo overexpression of CAMKV significantly delays disease progression in mice challenged with a street strain of RABV. Mechanistically, CAMKV interacts with both RABV P and SQSTM1, promoting SQSTM1-mediated selective autophagic clearance of P and thereby restricting RABV transcription and replication. Collectively, our findings establish CAMKV as a critical host antiviral effector that functions through selective autophagy, highlighting CAMKV as a promising molecular target for the development of novel therapeutics against lethal RABV infection. Abbreviation: 3-MA: 3-methyladenine; ABLV: Australian bat lyssavirus; ATG: autophagy related; AKT: AKT serine/threonine kinase; Baf-A1: bafilomycin A1; CAMKV: CaM kinase like vesicle associated; CAMK2: calcium/calmodulin dependent protein kinase II; co-IP: co-immunoprecipitation; CQ: chloroquine; DUVV: Duvenhage virus; DMSO: dimethyl sulfoxide; EBLV-1: European bat lyssavirus 1; ISG: interferon stimulated gene; LAMP1: lysosome associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; Mdivi-1: mitochondrial division inhibitor-1; MLD₅₀: 50% mouse lethal dose; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; qPCR: quantitative real-time polymerase chain reaction; RABV: rabies virus; SQSTM1/p62: sequestosome 1; WT: wild type.

Keywords:  Autophagy; CAMKV; phosphoprotein; rabies virus; virus replication

DOI:  https://doi.org/10.1080/15548627.2026.2699370
Mol Neurobiol. 2026 Jul 10. pii: 753. [Epub ahead of print]63(1):

SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.

Qingya Wu, Dengying Fan, Jianhui Ren, Yafang Xing, Zhengzheng Chen, Haochen Jin, Yisheng Lu, Xiaopeng Wang, Hua Zheng.

  Mitochondria, as the primary energy-generating organelles in neurons, play a pivotal role in regulating cellular metabolism. Given the post-mitotic nature and long lifespan of neurons, they are particularly vulnerable to the cumulative burden of mitochondrial damage. In response to various physiological and stress signals, a sophisticated mitochondrial quality control (MQC) system has evolved, which encompasses mitochondrial biogenesis, dynamics (fission and fusion), and mitophagy. This coordinated network acts as a critical surveillance mechanism to eliminate damaged components and maintain a healthy mitochondrial pool. The small ubiquitin-like modifier (SUMO) pathway, involving reversible SUMOylation and deSUMOylation, has emerged as a key regulator of MQC by directly modifying its core components. Dysregulation of the SUMO pathway disrupts mitochondrial homeostasis, and the resulting mitochondrial dysfunction is increasingly recognized as a central pathogenic mechanism in neurodegenerative diseases. This review systematically examines the role of the SUMO pathway in regulating MQC and its implications in the pathogenesis of Alzheimer's disease, Parkinson's disease, and Huntington's disease. Finally, we discuss the therapeutic potential and translational challenges of targeting the SUMO pathway for the treatment of neurodegenerative diseases.

Keywords:  Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Neurodegenerative diseases; SUMOylation

DOI:  https://doi.org/10.1007/s12035-026-06050-0
Autophagy. 2026 Jul 09.

NAD+ modulates REST isoform expression and its downstream mitophagy in Alzheimer's disease.

Maria J Lagartos-Donate, Beatriz Escobar-Doncel, Caroline Shi-Qi Zhang, Evandro Fei Fang.

  Repressor Element 1-Silencing Transcription factor (REST) emerges as a metabolism-sensitive transcriptional hub that supports basal mitophagy, mitochondrial quality, and synaptic function in neurons. In Alzheimer's disease, REST becomes mislocalized and functionally impaired, coinciding with early defects in mitochondrial quality control. Activation of the NAD+ -SIRT1 axis enhances REST nuclear activity, restores its mitochondrial and neuroprotective gene programs, and attenuates pathological and cognitive decline in experimental AD models. Our study highlights REST as a promising target to preserve mitochondrial and neuronal function.Abbreviations:Alzheimer's disease, AD; Repressor Element 1-Silencing Transcription factor, REST; Nicotinamide Adenine Dinucleotide, NAD+.

Keywords:  Alzheimer’s disease; NAD+; REST; SIRT1; transcriptional regulation

DOI:  https://doi.org/10.1080/15548627.2026.2701599
Free Radic Biol Med. 2026 Jul 07. pii: S0891-5849(26)00931-7. [Epub ahead of print]

Inhibiting VDAC1 oligomerization attenuated cerebral ischemia-reperfusion injury by promoting mitophagy via reduced LONP1 interaction.

Xiangna Guo, Huiyi Jiang, Yitian Lu, Yixin Lin, Junwei Liu, Zaisheng Qin, Tao Tao.

  Increasing evidence highlights the protective role of mitophagy in eliminating damaged mitochondria during ischemic stroke. As a mitochondrial gatekeeper, voltage-dependent anion channel 1 (VDAC1) mediates the elimination of damaged mitochondria through mitophagy. However, whether VDAC1 contributes to cerebral ischemia-reperfusion (I/R) injury and the underlying mechanisms remain unexplored. In this study, we demonstrated that inhibiting VDAC1 oligomerization reduced infarct volume and improved neurological function following cerebral I/R. We further confirmed that inhibiting VDAC1 oligomerization promoted mitophagy, thereby exerting neuroprotective effects. Additionally, VDAC1 knockdown restored mitochondrial membrane potential and decreased mitochondrial reactive oxygen species generation, thereby alleviating mitochondria damage in neurons subjected to oxygen-glucose deprivation /reoxygenation (OGD/R). Mechanistically, we identified the interaction between VDAC1 oligomers and Lon protease 1 (LONP1) as a critical regulator of mitophagy during cerebral I/R injury. Taken together, our findings provide novel insights into the regulation of mitophagy in cerebral I/R injury and suggest that VDAC1 represents a promising therapeutic target for ischemic stroke.

Keywords:  Cerebral ishemia-reperfusion injury; FUNDC1; LONP1; VDAC1; mitophagy

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.07.010
Autophagy. 2026 Jul 10. 1-21

Targeting the SNAI1-LAMP3 axis to restore lysosomal function and alleviate autophagic flux impairment to delay retinal degeneration.

Yuke Ji, Yanan Sun, Xiaosheng Huang, Jia Liang, Dong Fang, Weihua Yang, Lujia Feng, Shaochong Zhang.

  Retinal degenerative diseases are a leading cause of irreversible blindness. Their pathogenesis is intricately linked to oxidative stress-induced dysfunction of retinal pigment epithelial (RPE) cells and subsequent retinal degeneration. Macroautophagy/autophagy, a critical cellular degradation pathway, plays a vital role in maintaining RPE homeostasis, yet its dysregulation in retinal degenerative diseases remains poorly understood. In this study, we observed that sodium iodate (NaIO3), an oxidative stress inducer, triggered lysosomal dysfunction via lysosomal membrane permeabilization (LMP), thereby impairing autophagic flux in RPE cells and exacerbating retinal degeneration. RNA sequencing identified LAMP3 (lysosomal-associated membrane protein 3) as a downregulated gene following NaIO3 treatment. Functionally, LAMP3 overexpression alleviated NaIO3-induced LMP, improved lysosomal function, and alleviated autophagic impairment. Furthermore, upregulation of LAMP3 reduced oxidative stress and apoptosis in RPE cells, while alleviating retinal degeneration in a NaIO3-induced mouse model. Mechanistically, our data suggested that NaIO3 upregulated the transcription factor SNAI1, which acts as a transcriptional repressor of LAMP3. SNAI1 knockdown increased LAMP3 expression, thereby facilitating the recovery of lysosomal function and the alleviation of autophagic impairment. Collectively, our findings indicate that the SNAI1-LAMP3 axis contributes to the regulation of the autophagy-lysosomal pathway in retinal degeneration, highlighting a potential therapeutic target for delaying disease progression.Abbreviations: AMD: age-related macular degeneration; AO: acridine orange; Baf A1: bafilomycin A1; BAX: BCL2-associated X protein; BCL2: B cell leukemia/lymphoma 2; BSA: bovine serum albumin; CCK-8: cell counting kit-8; ChIP: chromatin immunoprecipitation; CM-H2DCFDA: chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; CTSD: cathepsin D; DAPI: 4',6-diamidino-2-phenylindole; DEGs: differentially expressed genes; DHE: dihydroethidium; EdU: 5-ethynyl-2'-deoxyuridine; ERG: electroretinography; GSEA: gene set enrichment analysis; H&E: hematoxylin and eosin; HsRPE: human primary retinal pigment epithelial; JC-1: 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide; LAMP1: lysosomal-associated membrane protein 1; LAMP2: lysosomal-associated membrane protein 2; LAMP3: lysosomal-associated membrane protein 3; LGALS3: lectin, galactose binding, soluble 3; LLOMe: leu-leu methyl ester; LMP: lysosomal membrane permeabilization; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MMP: mitochondrial membrane potential; NAC: N-acetyl-L-cysteine; NaIO3: sodium iodte; NC: negative control; OCT: optical coherence tomography; PCA: principal component analysis; PI: propidium iodide; qRT-PCR: quantitative real-time polymerase chain reaction; Rapa: rapamycin; ROS: reactive oxygen species; RP: retinitis pigmentosa; RPE: retinal pigment epithelium; RPE65: retinal pigment epithelium 65; siRNA: small interfering RNA; SNAI1: snail family zinc finger 1; SQSTM1/p62: sequestosome 1; TJP1/ZO-1: tight junction protein 1; ZNF135: zinc finger protein 135.

Keywords:  Autophagy; LAMP3; SNAI1; lysosomal membrane permeabilization; retinal degeneration

DOI:  https://doi.org/10.1080/15548627.2026.2700025
J Cell Biol. 2026 Sep 07. pii: e202511211. [Epub ahead of print]225(9):

Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.

Emily Glover, Beth Wiseman, Celyn Dugdale, Charlie Humphery, Lorena Sueiro Ballesteros, Lorna Hodgson, Kevin Wilkinson, Ian Collinson.

Mitochondrial protein import is critical for organelle biogenesis, maintenance, and regeneration-essential for cellular homeostasis. Import dysfunction compromises cellular energy supplies, which is damaging to cells, particularly those with high energetic demands like neurons. Previously, we have shown that import failure is rescued by intercellular mitochondrial transfer (IMT) via tunnelling nanotubes (TNTs) however, the fate of the transferred mitochondria and the mechanistic basis for rescue were unresolved. Here, we show that bidirectional mitochondrial trafficking between cells harboring import-defective and import-competent mitochondria is distinct in terms of their regulation and ensuing consequences. Transferred import-defective mitochondria are highly fragmented and destined for canonical lysosomal degradation. In contrast, reactive oxygen species (ROS)-producing mitochondria at the periphery of cells with import-competent mitochondria are transferred into neighboring cells undergoing import failure. These new arrivals then accumulate within previously uncharacterized "mitochondrial degradation bodies" (MDBs). We speculate that the cooperation of these distinct cases of TNT-mediated conventional and noncanonical "trans-mitophagy" instigates mitochondrial regeneration, and thereby rescues mitochondrial function.

DOI: https://doi.org/10.1083/jcb.202511211
Autophagy. 2026 Jul 06. 1-23

Targeting lysosomes with a novel chloroquine derivative induces irreversible lysosomal damage and disrupts autophagosome and lysosome assembly in cancer.

Nitish Chauhan, Ananda Guha Majumdar, Sujit Kumar Bhutia, Papiya Dey, Mahesh Subramanian, Birija Sankar Patro.

  Pancreatic ductal adenocarcinoma (PDAC) exhibits profound therapy resistance driven by lysosome-dependent nutrient recycling, metabolic adaptation, and stress tolerance. Current lysosome targeting agents such as chloroquine (CQ)/hydroxychloroquine (HCQ) show limited efficacy due to transient activity and dose-limiting-toxicities. To overcome these limitations, we developed lysostilbenes, a new class of hybrid small molecules combining the CQ pharmacophore with lysosome-disrupting stilbene analogs. Stilbene pharmacophore is the core structural component of resveratrol. Among the synthesized hybrids, lysostilbene-4 emerged as the lead candidate, demonstrating ~30-40-fold greater cytotoxicity against PDAC cells than parent compounds, while sparing nonmalignant cells. At nanomolar concentrations, lysostilbene-4 induced rapid, irreversible lysosomal membrane permeabilization (LMP), initiating a lysosome mitochondria apoptotic cascade via CTSB (cathepsin B) release, BID cleavage, BAX activation, and caspase-mediated apoptosis. In parallel, it abrogated lysosomal recovery by significantly reducing repair, lysophagy, autophagosome maturation, and uncoupling TFEB-driven transcriptional programs from effective lysosome biogenesis. Reduced TFEB mRNA expression correlated with poor overall-survival and disease-free-survival across multiple cancer patients, with a particularly strong association in pancreatic cancer patients. Using TFEB+/+ and TFEB-/- knockout pancreatic cancer cells we establish that lysostilbene-4 exerts severe cytotoxicity by inducing persistent lysosomal-damage and disrupting autophagosome-lysosome assembly, with vulnerability further amplified in TFEB-deficient cells. This finding underscores TFEB as a key determinant of lysosomal-resilience and a potential predictive biomarker. Importantly, lysostilbene-4 was well tolerated in preclinical mouse-models at supra-therapeutic doses without systemic-toxicity. These findings position lysostilbene-4 as a first-in-class lysosome-targeting therapeutic that enforces sustained lysosomal collapse while compromising adaptive recovery-mechanisms, providing a mechanistically precise and safe strategy against PDAC.Abbreviations: ALG: autophagy-lysosome genes; AMPK: AMP-activated protein kinase; CASM: conjugation of ATG8s to single membranes; CTSB: cathepsin B; LGALS3: galectin 3; LMP: lysosomal membrane permeabilization; LS: lysostilbene; MTOR: mechanistic target of rapamycin kinase; PDAC: pancreatic ductal adenocarcinoma; TCGA: The Cancer Genome Atlas; TFEB: transcription factor EB; ULK1: unc-51 like autophagy activating kinase 1.

Keywords:  Chloroquine; dihydroxystilbene; lysophagy; lysosome repair; lysostilbene; resveratrol

DOI:  https://doi.org/10.1080/15548627.2026.2693263
Inflammation. 2026 Jul 07.

Mitophagy in Metabolic Dysfunction-Associated Fatty Liver Disease: Mechanisms, Regulatory Networks, and Therapeutic Perspectives.

Zhiqiu Liu, Shuyang Zhang, Tianshu Zeng.

  Metabolic dysfunction-associated fatty liver disease (MASLD) represents the most prevalent chronic liver disorder globally, with pathogenesis closely linked to insulin resistance, obesity, and gut microbiota dysbiosis. Mitochondrial dysfunction is central to MASLD progression, and mitophagy-a selective form of autophagy that clears damaged mitochondria-plays a crucial role in maintaining cellular homeostasis. This review systematically delineates the molecular mechanisms, regulatory networks, and therapeutic implications of mitophagy in MASLD. We first outline the core machinery of mitophagy, encompassing both ubiquitin-dependent and ubiquitin-independent pathways. We then discuss how impaired mitophagy drives the disease progression of MASLD from the perspective of different hepatic cell types. Furthermore, we summarize the multilayered upstream regulatory network governing mitophagy in the context of MASLD, involving key signaling pathways, metabolic reprogramming, inflammatory cues, epigenetic modifications, and intercellular crosstalk. Finally, we examine therapeutic strategies targeting mitophagy-including clinical and preclinical agents, natural compounds, physical interventions, and emerging technologies-and highlight the challenges posed by its dualistic nature. Moving forward, integrating spatiotemporal dynamics with precision targeting will be essential to translate mitophagy modulation from mechanistic insight into viable clinical therapies for MASLD.

Keywords:  MASH mitophagy inflammation intercellular crosstalk regulatory network therapeutic targets; MASLD

DOI:  https://doi.org/10.1007/s10753-026-02548-w
Aging Cell. 2026 Jul;25(7): e70624

Metabolic Kinases as Regulators of Inter-Organelle Communication in Aging and Age-Related Diseases.

Md Riad Chowdhury, Jae-Han Jeon, Dipanjan Chanda.

  Cellular aging is accompanied by progressive alterations in metabolic homeostasis, stress adaptation, and organelle function. Increasing evidence suggests that functional coordination among membrane-bound organelles, including mitochondria, the endoplasmic reticulum (ER), lysosomes, peroxisomes, and the Golgi apparatus, contributes to cellular homeostasis during aging. However, the mechanisms linking kinase signaling to specific inter-organelle contact sites or communication pathways remain incompletely defined. In this review, we discuss current evidence linking major metabolic and stress-responsive kinases, including AMPK, pyruvate dehydrogenase kinases (PDKs), mTOR, AKT, and PERK, to organelle coordination in aging and age-related diseases. These kinases regulate mitochondrial dynamics, metabolic flux, calcium and lipid handling, autophagy, lysosomal function, proteostasis, and vesicular trafficking. In some contexts, kinase signaling intersects with defined organelle interfaces, such as mitochondria-associated ER membranes, whereas in many cases the effects on inter-organelle communication are indirect or inferred from broader changes in organelle function. We further discuss how kinase dysregulation may contribute to age-associated defects in mitochondria-ER, mitochondria-lysosome, mitochondria-peroxisome, and ER-Golgi coordination in neurodegeneration, cardiometabolic disease, cellular senescence, and inflammaging. By distinguishing direct contact-site regulation from indirect functional coordination, this review highlights kinase-regulated organelle communication as an emerging, but still incompletely resolved, framework for understanding cellular decline during aging.

Keywords:  age‐related diseases; aging; inter‐organelle communication; metabolic kinases; mitochondrial quality control

DOI:  https://doi.org/10.1111/acel.70624
Autophagy. 2026 Jul 05. 1-27

Hypoxia-preconditioned dental pulp stem cells alleviate acetaminophen-induced liver failure via promoting MYC-HIF1A/HIF-1α-BNIP3-mediated mitophagy.

Junyi Li, Qianyu Yang, Pengcheng Pang, Ye Liu, Xiaojing Liu, Wanyang Zhong, Rui Zhang, Wenao Sun, Yan He, Qingsong Ye.

  Acetaminophen (APAP)-induced acute liver injury (AILI) is a prevalent clinical liver condition caused mostly by oxidative stress and mitochondrial damage. Dental pulp stem cells (DPSCs) possess antioxidant, anti-inflammatory, and immunomodulatory capabilities, demonstrating significant potential in liver diseases. However, during in vitro culture, they are typically maintained under normoxic conditions (21% O2), which is very different from the hypoxic oxygen level that is found in vivo. It remains unclear whether hypoxic-conditioned dental pulp stem cells (Hyp-DPSCs) exhibit superior therapeutic effects compared to normoxic-conditioned dental pulp stem cells (Nor-DPSCs). This study demonstrated that 24-h exposure to 1% O2 significantly enhanced HIF1A/HIF-1α expression in DPSCs. It promoted mitophagy through the MYC-HIF1A-BNIP3 pathway, enhancing mitochondrial shape and function while reducing oxidative stress in DPSCs. Furthermore, in vitro and in vivo experiments demonstrated that Hyp-DPSCs were far more potent than Nor-DPSCs in boosting the expression of hepatic antioxidant factors and enhancing macroautophagy/autophagy to reduce AILI. These findings revealed that hypoxia activated mitophagy in DPSCs, enhancing their therapeutic efficacy against AILI and providing a novel strategy for stem cell-based AILI treatment.Abbreviations: AILI: acetaminophen-induced acute liver injury; ANOVA: analysis of variance; APAP: acetaminophen; BAX: BCL2 associated X, apoptosis regulator; BCL2: BCL2 apoptosis regulator; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; CASP3: caspase 3; CAT: catalase; CCK-8: cell counting kit-8; CM: conditioned medium; COX4I1: cytochrome c oxidase subunit 4I1; CPT1A: carnitine palmitoyltransferase 1A; CQ: chloroquine; DPSCs: dental pulp stem cells; ELISA: enzyme-linked immunosorbent assay; GO: Gene Ontology; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic - pyruvic transaminase; GPX4: glutathione peroxidase 4; GSH: glutathione; Hyp-DPSCs: hypoxic-conditioned dental pulp stem cells; H&E: hematoxylin and eosin; HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha; HMOX1/HO-1: heme oxygenase 1; HUVECs: human umbilical vein endothelial cells; IF: immunofluorescence; IHC: immunohistochemistry; IL1B/IL-1β: interleukin 1 beta; IL6: interleukin 6; i.p.: intraperitoneally; i.v.: intravenous injection; KEGG: Kyoto Encyclopedia of Genes and Genomes; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MSCs: mesenchymal stem cells; MYC: MYC proto-oncogene, bHLH transcription factor; NAC: N-acetylcysteine; NAPQI: N-acetyl-p-benzoquinone imine; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; Nor-DPSCs: normoxic-conditioned dental pulp stem cells; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; PLIN2: perilipin 2; PINK1: PTEN induced kinase 1; PPARA/PPARα: peroxisome proliferator activated receptor alpha; PPARG/PPARγ: peroxisome proliferator activated receptor gamma; ROS: reactive oxygen species; SEM: standard error of the mean; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TNF/TNF-α: tumor necrosis factor; TOMM20: translocase of outer mitochondrial membrane 20; VDAC1: voltage dependent anion channel 1; WB: western blot.

Keywords:  Acetaminophen-induced acute liver injury; BNIP3; HIF1A/HIF-1α; hypoxia; MYC; dental pulp stem cells; mitophagy

DOI:  https://doi.org/10.1080/15548627.2026.2694664
FEBS J. 2026 Jul 07.

Stimulating proteasomal degradation in human proteinopathies.

Maria E Gierisch, Enrica Barchi, Nico P Dantuma.

  The ubiquitin-proteasome system (UPS) comprises hundreds of proteins that orchestrate ubiquitin-dependent proteasomal degradation and represents a powerful therapeutic target for modulating intracellular protein turnover. Due to its central role in preventing the accumulation of misfolded and dysfunctional proteins, enhancing or suppressing UPS activity offers clinical potential across a wide spectrum of diseases. While oncology has successfully capitalized on this vulnerability through the development of proteasome inhibitors for the treatment of hematological malignancies, efforts to generate clinically relevant UPS activators have progressed more slowly. Bridging this therapeutic gap could be particularly beneficial for neurodegenerative diseases and other proteinopathies, where accelerating the removal of misfolded and aggregation-prone proteins may help counteract their progressive accumulation and delay, or prevent the onset of symptoms. In this review, we summarize the progress made so far toward finding strategies to boost UPS function through genetic or small-molecule interventions.

Keywords:  aggregation; neurodegeneration; proteasome; protein degradation; ubiquitin

DOI:  https://doi.org/10.1111/febs.70638
Stem Cell Rev Rep. 2026 Jul 09.

Cell-Type-Specific Calibration of Mitochondrial Ubiquitination in Stem Cell Fate Decisions.

Hao-Cheng Liu, Si-Yuan Chen, Nan-Nan Yu, Mei-Hua Jin, Hu-Nan Sun, Ying-Hao Han.

  Stem cell fate decisions-whether to self-renew, differentiate, or senesce-are inextricably linked to the metabolic identity and quality-control status of mitochondria. The ubiquitin-proteasome system and selective autophagy pathways assemble into an integrated surveillance network at the mitochondrial outer membrane that gauges organelle health, sculpts morphology, and transduces metabolic information into lineage-determining transcriptional programmes. This Review examines how the ubiquitination machinery-spanning the canonical PINK1-Parkin axis and non-Parkin E3 ligases including MARCH5, MUL1, and the emerging Cullin-RING component RBX2-orchestrates outer-membrane protein degradation, mitochondria-derived vesicle biogenesis, and the balance between fusion and fission. We discuss how these post-translational events govern stem cell identity across haematopoietic, muscle, neural, mesenchymal, and pluripotent compartments. Recent 2024-2025 advances include an Nicotinamide Adenine Dinucleotide (NAD+)-dependent metabolic checkpoint governing haematopoietic stem cell activation and aging, the crystallographic resolution of USP30 inhibitor binding, molecular glue activators that allosterically enhance Parkin RING-domain activity, ClpP-based mitochondria-targeted PROTAC platforms, and HIF-1α/BNIP3-mediated pharmacological rejuvenation of aged mesenchymal stem cells. We further discuss the WAC-PINK1-Parkin axis in mesenchymal stem cell aging, the bidirectional interplay between reactive oxygen species and E3 ligase activity, and the ACC1-FIS1 ubiquitination axis. Finally, we consider the cell-type-specific calibration of mitochondrial ubiquitination as a unifying principle for precision therapeutics and the inverted quality-control logic exploited by cancer stem cells. We propose that the cell-type-specific calibration of mitochondrial ubiquitination-whereby identical molecular events carry divergent functional consequences across stem cell compartments-offers a unifying framework for precision therapeutics.

Keywords:  Mitochondrial dynamics; Mitochondrial ubiquitination; Mitophagy; PINK1-Parkin; Stem cell fate

DOI:  https://doi.org/10.1007/s12015-026-11189-3
Mol Neurobiol. 2026 Jul 06. pii: 746. [Epub ahead of print]63(1):

Curcumin Attenuates Cuproptosis via Activating Autophagy Through Inhibition of the AKT/mTOR/P70S6K-Signaling Pathway in Parkinson's Disease Models.

Feng Ren, Yanpeng Sun, Man Wang, Kun Zheng, Chao Zuo, Hui Shang, Jing Zhu.

  This research surveyed the therapeutic potential of curcumin (Cur) in Parkinson's disease (PD), focusing on its effects on cuproptosis and underlying molecular mechanisms. A MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced mouse model and a MPP+ (1-methyl-4-phenylpyridinium)-treated PC12 cell model were used in this study. In vivo, Cur treatment significantly mitigated MPTP-treated dyskinesia and lessened the damage of dopaminergic (DA) neurons in SNpc. Additionally, Cur reversed MPTP-induced changes by increasing TH (tyrosine hydroxylase) expression and decreasing α-syn (α-synuclein) accumulation in the SN. In vitro, Cur mitigated MPP+-treated apoptosis and the cytotoxicity of differentiated PC12 cells. Furthermore, Cur reversed MPTP/MPP+-induced changes in the cuproptosis-related protein expression, including DLAT (dihydrolipoamide S-acetyltransferase), FDX1 (ferredoxin 1), and upregulating SLC31A1 (solute carrier family 31 member 1) and HSP70 (heat shock protein 70). 3-MA (3-methyladenine) reversed Cur-mediated expression levels of DLAT, FDX1, SLC31A1, and HSP70 in the PD models. Mechanistically, Cur decreased the expression of p-AKT (p-protein kinase B), p-mTOR (p-mammalian target of rapamycin), and p-P70S6K (p-70 KDa ribosomal protein S6 kinase‌) in the PD models, suggesting it has an inhibitory effect on the AKT/mTOR/P70S6K signaling pathway. Furthermore, pretreatment with SC79 (an AKT activator) reversed Cur-induced autophagy activation, supporting the role of this pathway in Cur-mediated neuroprotection. Cur protected against DA neuronal loss by modulating the interplay between cuproptosis and autophagy via the suppression of the AKT/mTOR/P70S6K. The study findings provide novel insights into the mechanism of Cur's neuroprotective effect, highlighting the AKT/mTOR/autophagy/cuproptosis axis as a potential target and Cur as a medicant for PD management.

Keywords:  AKT/mTOR/P70S6K; Autophagy; Cuproptosis; Curcumin; Parkinson’s disease

DOI:  https://doi.org/10.1007/s12035-026-06048-8
Ageing Res Rev. 2026 Jul 08. pii: S1568-1637(26)00240-0. [Epub ahead of print]121 103248

The autophagy-senescence-inflammasome axis: A novel triad in neurodegenerative diseases?

Surendar Ellappan, Punit Prasanna Kujur, Amal Chandra Mondal.

  Chronic neuroinflammation is a defining feature of brain ageing and neurodegenerative disorders, yet the molecular mechanisms responsible for its persistence remain incompletely understood. Although autophagy dysfunction, glial senescence, and inflammasome activation are well-established contributors to progressive neurodegeneration, these processes are often analysed independently or through pairwise interactions, leaving their collective contribution to persistent neuroinflammation and disease progression insufficiently defined. Here, we synthesise emerging evidence supporting an integrated 'Autophagy-Senescence-Inflammasome (ASI) axis', in which reciprocal interactions among impaired autophagy, senescent glia, and inflammasome signalling establish a self-sustaining cycle of neuroinflammation. We discuss how defective autophagy promotes mitochondrial dysfunction, oxidative stress, and danger signalling, while senescent astrocytes and microglia amplify inflammatory responses through the senescence-associated secretory phenotype (SASP). These intertwined processes converge on chronic inflammasome activation, with mitochondrial dysfunction emerging as a central mechanistic hub. Evidence across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and chronic neuropathic pain highlight the broad relevance of this pathological network. We further analyse current therapeutic strategies targeting autophagy, senescence, and inflammasome pathways, emphasising the limitations of single-target approaches and the potential of multi-target interventions. By integrating these processes into a unified framework, this review provides new insights into the possible molecular mechanisms underlying neuroinflammaging and identifies the 'ASI axis' as a promising target for neurodegenerative disease-modifying therapies.

Keywords:  Autophagy; Glial senescence; Inflammasome; Mitochondrial dysfunction; Neurodegeneration; Neuroinflammation

DOI:  https://doi.org/10.1016/j.arr.2026.103248
Mol Cancer. 2026 Jul 08.

Autophagy in cancer - functional plasticity, therapeutic paradox, and the road to precision modulation: a comprehensive review.

Jingjing Liu, Peng Wu, Dongyu Li, Xuanyu Gu, Bohui Zhao, Ruijie Ma, Binghua Tan, Dexin Shang, Junhan Zhou, Chuqi Lin, Nan Sun, Chaoqi Zhang, Jie He.

  Autophagy is an evolutionarily conserved lysosomal degradation pathway. In cancer, its role is paradoxical: it functions as a tumor-suppressive gatekeeper during initiation in part by preserving genomic stability, but it is frequently co-opted by established tumors to maintain metabolic fitness and therapeutic resistance. Early clinical efforts using broad, non-selective lysosomal inhibition (e.g., chloroquine) produced mixed outcomes and toxicities, prompting a paradigm shift toward modular, context-specific modulation.This review synthesizes the dynamic spatiotemporal evolution of autophagy in tumorigenesis, and characterizes it as an adaptable evolutionary trajectory governed by stress, tumor genotype, and microenvironmental context. We outline four conceptual pillars: genotype-defined modular networks, dynamic spatiotemporal adaptation, autophagy as an immunometabolic rheostat, and rational therapeutic modulation. Importantly, autophagy exerts cell-type-specific effects-promoting immune evasion in tumor cells while remaining indispensable for lymphocyte fitness. To address this paradox, we evaluate the transition from empirical global blockade to precision-guided intervention, including pathway-selective modulators, exploitation of selective vulnerabilities, and advanced targeted degradation technologies. Autophagy in cancer is a highly dynamic, context-dependent variable. Therapeutic control requires movement beyond universal flux inhibition toward pathway-specific, biomarker-guided interventions that match a tumor's distinct autophagic dependencies. Integration of dynamic monitoring with precise delivery systems may allow active modulation of the tumor microenvironment, transforming autophagy from a tumor resilience mechanism into an exploitable therapeutic vulnerability.

Keywords:  Autophagy plasticity; Cancer metabolism; Immune regulation; Precision oncology; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-026-02633-6
Food Chem Toxicol. 2026 Jul 10. pii: S0278-6915(26)00344-3. [Epub ahead of print] 116270

Triptolide-induced hepatotoxicity is mediated by NLRP3-dependent pyroptosis and inhibited by mitophagy.

Yuerui Su, Pengcheng Li, Kun Zhou, Yinxia Chang, Zhihua Luan, Bo Han, Huifang Li, Jinhong Ren, Haixue Zhang, Yanming Wei.

  This study investigated the regulatory effects of triptolide on PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy and NOD-like receptor family pyrin domain containing 3 (NLRP3)-mediated pyroptosis. Furthermore, it aimed to elucidate the potential relationship between mitophagy and pyroptosis in triptolide-induced hepatotoxicity. We established in vitro and in vivo models using a human normal hepatic cell line, HL7702, and C57BL/6J mice treated with triptolide. Furthermore, mitophagy inhibition experiments were performed using cyclosporin A, chloroquine, or PINK1 knockdown. The results revealed that triptolide induced severe hepatic cell damage accompanied by mitochondrial impairment. PINK1/Parkin-mediated mitophagy was concurrently induced, which manifested via increased levels of PINK1, Parkin, and microtubule-associated protein light chain 3II, and decreased p62. Moreover, triptolide increased the levels of NLRP3-mediated pyroptotic markers, including NLRP3, caspase-1, cleaved caspase-1, and gasdermin D N-terminal fragment, and promoted the extracellular release of IL-1β and IL-18. Notably, mitophagy inhibition further augmented the triptolide-induced hepatic cell pyroptosis and worsened hepatic damage. Taken together, our results indicate that the triptolide-activated pyroptosis induces hepatotoxicity, which is subsequently suppressed by mitophagy. Therefore triptolide-induced hepatotoxicity is mediated by NLRP3-dependent pyroptosis and inhibited by mitophagy.

Keywords:  Hepatotoxicity; Mitophagy; NLRP3 inflammasome; PINK1/Parkin pathway; Pyroptosis; Triptolide

DOI:  https://doi.org/10.1016/j.fct.2026.116270
Sci Transl Med. 2026 Jul 08. 18(857): eadv7705

Targeting of CH25H to boost p62-dependent autophagic degradation of α-synuclein in cell and mouse models of Parkinson's disease.

Xiwei Zhang, Ruixue Han, Wen Zhang, Shenhan Xu, Yueping Wang, Min Wang, Renhong Du, Yang Liu, Luping Zhang, Cong Wang, Kezhong Zhang, Gang Hu, Huae Xu, Lei Cao, Ming Lu.

Insufficient understanding of α-synuclein turnover mechanisms has impeded successful clinical translation for Parkinson's disease (PD). Here, we pinpointed cholesterol 25-hydroxylase (CH25H) as a pivotal regulator of α-synuclein degradation. Through bulk RNA sequencing of substantia nigra tissue from the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, along with reanalysis of published datasets from induced pluripotent stem cell-derived astrocytes of patients with PD, we observed an elevated CH25H expression in PD-associated astrocytes. This finding was validated by combined fluorescence in situ hybridization for Ch25h and immunofluorescence staining for GFAP in mouse substantia nigra sections. Conditional knockout or knockdown of astrocytic Ch25h alleviated PD-like motor deficits and reduced dopaminergic neuronal loss in MPTP and α-synuclein preformed fibril (PFF) mouse models. Using 4D label-free proteomics and molecular docking approaches, we uncovered a shared binding domain on p62 where both CH25H and α-synuclein interact. Proximity ligation assays in cultured astrocytes showed that Ch25h overexpression promoted formation of p62/CH25H complex, whereas it inhibited p62/α-synuclein interaction. Conversely, Ch25h knockdown enhanced p62/α-synuclein complex formation and facilitated α-synuclein degradation. 25-Hydroxycholesterol, the enzymatic by-product of CH25H, did not affect the expression of α-synuclein in astrocytes, suggesting an activity-independent influence of CH25H on α-synuclein clearance. In addition, treatment with a p62 polypeptide (60 to 90 amino acids) effectively facilitated α-synuclein clearance by sequestering free CH25H in both cultured astrocytes and mice in the PFF model. Collectively, our study provides insights into the mechanisms underlying α-synuclein turnover and suggests promising avenues for disease-modifying interventions in synucleinopathies.

DOI: https://doi.org/10.1126/scitranslmed.adv7705
Mol Cell. 2026 Jul 09. pii: S1097-2765(26)00415-6. [Epub ahead of print]

The UFSP2-ODR4 complex spatially confines and dynamically controls UFM1 deconjugation to safeguard neuronal proteostasis.

Gaoxin Mao, Sota Ito, Ryosuke Ishimura, Jun-Ichi Sakamaki, Ryohei Sasaki, Takefumi Uemura, Kei-Ichi Ishikawa, Satoko Komatsu-Hirota, Wado Akamatsu, Manabu Abe, Satoshi Waguri, Sunita Bijarnia-Mahay, Nobuo N Noda, Toshifumi Inada, Masaaki Komatsu.

  The ubiquitin-fold modifier 1 (UFM1) pathway is essential for endoplasmic-reticulum-associated ribosome quality control (ER-RQC) through UFMylation of the 60S ribosomal protein RPL26, but the regulation and physiological significance of UFM1 deconjugation remain poorly understood. Here, we identify the ER-anchored UFSP2-ODR4 complex as a spatially confined deUFMylation module critical for neuronal proteostasis. Structural modeling and biochemical analyses show that ODR4 recruits UFSP2 to the ER, enabling efficient deUFMylation of RPL26. Disruption of the UFSP2-ODR4 interaction causes the accumulation of UFMylated RPL26 and defective ER-RQC. Neural progenitor-specific knockin mice expressing a catalytically inactive UFSP2 mutant exhibit perinatal lethality, microcephaly, and neuronal apoptosis. We also identify a patient with biallelic UFC1 mutations that enhance UFL1 binding and induce hyper-UFMylation of RPL26 in patient-derived neurons. These findings establish spatially confined deUFMylation as a critical mechanism for safeguarding neuronal proteostasis.

Keywords:  ER-RQC; ODR4; UFC1; UFM1; UFSP2; endoplasmic-reticulum-ribosome quality control; neurodevelopmental disorders; neuronal proteostasis; ribosomal protein RPL26

DOI:  https://doi.org/10.1016/j.molcel.2026.06.026
EMBO J. 2026 Jul 08.

Local autophagy impairment triggers brain-wide presynaptic remodeling and resilience.

David Toppe, Sheng Huang, Janine Lützkendorf, Pin-Lian Jiang, Raquel Suárez-Grimalt, Alexander Neumann, Zhiying Zhao, Péter Lőrincz, Lisa Scheunemann, Gábor Juhász, Fan Liu, Marta Maglione, Stephan J Sigrist.

Neural circuits must remain functionally stable while adapting to changing demands and levels of stress. While this balance is thought to rely on plasticity programs integrating molecular and activity-dependent signals, mechanistic models of how such adaptations are orchestrated remain limited. Here, we show that impairment of autophagy in the Drosophila mushroom body (MB) induces brain-wide, post-transcriptional remodeling of presynaptic active zones, characterized by increased expression levels of active zone scaffold proteins, reduced abundance of calcium channel subunits, and elevated levels of Shaker-type potassium channels. This remodeling promotes organismal resilience, as reflected by increased sleep and extended lifespan. Mechanistically, early-life activation of this program is sufficient to extend lifespan, identifying synaptic remodeling as a causal driver of adaptive responses. MB-specific autophagy disruption further leads to non-cell autonomous accumulation of autophagic substrates across the brain, consistent with a system-level proteostatic imbalance in which degradative pathways remain active, but appear insufficient to match cargo load. Our findings identify autophagy in the mushroom body as a key regulator of brain-wide synaptic architecture and resilience, and establish a genetically tractable model for how local proteostatic impairment can trigger adaptive, system-level circuit remodeling.

DOI: https://doi.org/10.1038/s44318-026-00847-4