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Results for “Autophagy”

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At least 19 recordsLinked to original sources

PubMed2026

Respiratory viruses activate autophagy via the IFN-STAT1/STAT5B-SOCS1 axis.

Autophagy is an ancient catabolic process that has emerged as part of innate immunity. Upon infection, autophagy is activated but the key factors responsible remained unclear. Here, we show that interferon (IFN) released during viral infections subsequently activates autophagy via STAT1/5B-mediated upregulation of Suppressor of Cytokine Signaling 1 (SOCS1). Our data show that scavenging of IFNs diminishes autophagy induced by several respiratory viruses. All types of IFN (I, II and III) mediated robust autophagic flux activation in both cell lines and primary human lung fibroblasts in a JAK1-3 dependent manner. Depletion or pharmacological inhibition of individual signal transducer and activator of transcription (STAT) transcription factors demonstrated that both STAT1 and STAT5B are required for IFN-induced autophagy. Upon IFN stimulation STAT1 and STAT5B associate and translocate to the nucleus. Transcriptome analyses revealed that most known anti-viral IFN-stimulated genes (ISGs) remain induced to high levels upon inhibition of STAT5 expect for a small subset of ISGs, among them SOCS1. Overexpression of SOCS1 stimulated autophagy, whereas its depletion impaired IFN-induced autophagy. Successful viruses like measles virus (MeV) or respiratory syncytial virus (RSV) evolved strategies to exploit autophagy to promote their own replication. Uncoupling IFN-mediated ISG defenses from autophagy induction by STAT5 inhibition reduced virus-induced autophagy, and inhibited efficient replication of autophagy-dependent MeV and RSV. Overexpression of SOCS1 upon STAT5 inhibition largely rescued both infection-induced autophagy and viral replication. Taken together, our data show that IFN promotes autophagy via STAT1/STAT5B-SOCS1 in viral infections and reveal that targeting of this axis allows inhibition of autophagy-dependent viruses without compromising innate immune defenses.

Humans↗

PubMed2023

Autophagy supports mitochondrial metabolism through the regulation of iron homeostasis in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) cells maintain a high level of autophagy, allowing them to thrive in an austere microenvironment. However, the processes through which autophagy promotes PDAC growth and survival are still not fully understood. Here, we show that autophagy inhibition in PDAC alters mitochondrial function by losing succinate dehydrogenase complex iron sulfur subunit B expression by limiting the availability of the labile iron pool. PDAC uses autophagy to maintain iron homeostasis, while other tumor types assessed require macropinocytosis, with autophagy being dispensable. We observed that cancer-associated fibroblasts can provide bioavailable iron to PDAC cells, promoting resistance to autophagy ablation. To overcome this cross-talk, we used a low-iron diet and demonstrated that this augmented the response to autophagy inhibition therapy in PDAC-bearing mice. Our work highlights a critical link between autophagy, iron metabolism, and mitochondrial function that may have implications for PDAC progression.

Animals↗

PubMed2026

Autophagy activation in granulosa cells as a mechanism of astaxanthin action: evidence from a pilot randomised trial in PMOS-associated infertility.

Astaxanthin (AST) has been reported to influence oxidative stress, endoplasmic reticulum stress, and apoptosis in women with polyendocrine metabolic ovarian syndrome (PMOS), formerly referred to as polycystic ovary syndrome (PCOS), but its effects on granulosa-cell (GC) autophagy remain unclear. Given the central role of autophagy in follicular development, this triple-blind, placebo-controlled pilot randomised trial evaluated whether AST modulates autophagy-related signalling in GCs and how these molecular effects relate to ovarian response. Fifty women with PMOS-related anovulatory infertility were enrolled between November 2023 and September 2024 and received AST (12 mg/day) or placebo for six weeks prior to oocyte retrieval; forty-four completed the study (21 AST, 23 placebo). Primary exploratory endpoints were molecular markers of adenosine monophosphate-activated protein kinase (AMPK)-autophagy signalling, and primary clinical outcomes included ovarian response indicators and cleavage stage embryo quality. AST supplementation increased autophagy-related gene 7 (ATG7) expression, enhanced autophagy flux, reduced apoptosis, and showed a trend toward increased AMPK activation. Before adjustment, AST improved oocyte maturity rate (OMR) and increased mature (metaphase II; MII) oocyte yield. After adjusting for age, body mass index, and anti-mullerian hormone level, total oocyte and MII oocyte yields remained significantly higher with AST, while OMR became non-significant. Among embryology outcomes, both the top-ranking embryo rate and the number of embryos suitable for cryopreservation were significantly higher with AST after adjustment. Pregnancy outcomes were numerically higher but not statistically significant. This pilot trial suggests that AST activates autophagy- and apoptosis-related pathways in GCs and may enhance oocyte competence and embryo quality in PMOS. Larger studies are needed to confirm these mechanistic and clinical effects.

Female↗

PubMed2024

Identification of autophagy-related genes as potential biomarkers correlated with immune infiltration in bipolar disorder: a bioinformatics analysis.

BACKGROUND: Bipolar disorder (BPD) is a kind of manic and depressive phase alternate episodes of serious mental illness, and it is correlated with well-documented cortical brain abnormalities. Emerging evidence supports that autophagy dysfunction in neuronal system contributes to pathophysiological changes in neurological disease. However, the role of autophagy in bipolar disorder has rarely been elucidated. This study aimed to identify the autophagy-related gene as a potential biomarker Correlated to immune infiltration in BPD. METHODS: The microarray dataset GSE23848 and autophagy-related genes (ARGs) were downloaded. Differentially expressed genes (DEGs) between normal and BPD samples were screened using the R software. Machine learning algorithms were performed to screen the significant candidate biomarker from autophagy-related differentially expressed genes (ARDEGs). The correlation between the screened ARDEGs and infiltrating immune cells was explored through correlation analysis. RESULTS: In this study, the autophagy pathway was abundantly enriched and activated in BPD, as indicated by Pathway enrichment analysis. We identified 16 ARDEGs in BPD compared to the normal group. A signature of 4 ARDEGs (ERN1, ATG3, CTSB, and EIF2AK3) was screened. ROC analysis showed that the above genes have good diagnostic performance. In addition, immune correlation analysis considered that the above four genes significantly correlated with immune cells in BPD. CONCLUSIONS: Autophagy - immune cell axis mediates pathophysiological changes in BPD. Four important ARDEGs are prospective to be potential biomarkers associated with immune infiltration in BPD and helpful for the prediction or diagnosis of BPD.

Bipolar Disorder↗

PubMed2026

Autophagy in the Regulation of Placental Development: From Trophoblast Differentiation to Metabolic Stress Adaptation.

Successful pregnancy depends on precise placental development, where trophoblast differentiation, syncytialization, invasion, and adaptation to metabolic stress are critical. Autophagy, a lysosome-mediated degradation pathway, has emerged as an important regulator of cellular homeostasis, yet its integrated role in trophoblast fate and functions has not been comprehensively summarised. This review synthesises current evidence on autophagy's functions throughout placentation, from trophoblast differentiation to syncytialization and extravillous trophoblast invasion. We examine how autophagy enables cellular remodelling during differentiation, supports metabolic adaptation under hypoxia and nutrient stress, and maintains mitochondrial quality control through selective mitophagy. Autophagy is essential for syncytiotrophoblast formation via endoplasmic reticulum stress-coordinated activation and p53 downregulation. However, its effects on trophoblast invasion are context-dependent, influenced by oxygen tension, autophagic flux completeness, and differentiation state, which can potentially be shaped by parent-offspring genetic conflicts through genomic imprinting. Both excessive and insufficient autophagy contribute to pregnancy complications, including pre-eclampsia, foetal growth restriction, gestational diabetes mellitus, preterm birth, recurrent spontaneous abortion and obstetric antiphospholipid syndrome through distinct molecular mechanisms. Autophagy functions as a dynamically tuned homeostatic mechanism in placental development. Understanding condition-specific autophagy dysregulation is thereby crucial for improving pregnancy outcomes.

Autophagy↗

PubMed2026

Activation of pro-survival autophagy by a small molecule promoting p62 oligomerization.

Autophagy is a critical mechanism of cellular quality control, orchestrated by selective autophagy receptor (SAR) proteins. Pharmacologically enhancing the cargo-targeting capacity of SARs presents an attractive but underexplored strategy for the precise therapeutic activation of autophagy. Here, we characterize SQ-1, a small-molecule activator of autophagy that engages the prototypical SAR protein p62/sequestosome-1 (SQSTM1). We show that SQ-1 sensitizes p62 to oxidation and promotes its disulfide-mediated oligomerization in response to mitochondrial reactive oxygen species (ROS). This ROS-dependent activation of p62-mediated selective autophagy enhances the clearance of ROS-generating mitochondria and restores cell viability in models of Niemann-Pick type C1 disease, which is marked by impaired autophagic flux. In summary, the unique mode of action of SQ-1 enables self-regulated autophagy activation, offering a potential therapeutic strategy for lysosomal storage disorders and a broader spectrum of age-related diseases characterized by defective autophagy.

Niemann-Pick type C1 disease↗

PubMed2025

Corticotropin-releasing hormone inhibits autophagy by suppressing PTEN to promote apoptosis in dermal papilla cells.

BACKGROUND: Stress-related hair loss is on the rise, largely due to escalating levels of stress-related corticotropin-releasing hormone (CRH) through poorly defined mechanisms. CRH-mediated activation of corticotropin-releasing hormone receptors (CRHRs) on dermal papilla cells (DPCs) is a likely cause of stress-related hair loss. The aim of the study is to elucidate the key mechanisms of alopecia caused by CRH and provide potential new targets for the treatment of stress-related hair loss. METHODS: 4D label-free quantitative proteomics of DPCs and the chronic unpredictable mild stress mouse (CUMS) model were used to explore the relationship and mechanism between CRH, DPCs and hair regeneration. RESULTS: CRH initially downregulated PTEN to suppress autophagy, leading to DPC apoptosis. Overexpression of PTEN enhanced autophagy and mitigated CRH-dependent DPC apoptosis. CRH inhibited PTEN and activated the PI3K/AKT/mTOR pathway, whereas rapamycin inhibited this pathway and activated autophagy, consequently lowering apoptosis, suggesting that increased susceptibility to apoptosis is caused by decreased autophagy. CUMS-induced hair growth disruption is accompanied by an increase in CRHRs and a decrease in PTEN levels within the dermal papilla. Intracutaneous injection of CRH impeded hair regeneration and decreased PTEN in mice, concurrent with inhibition of autophagy and increased apoptosis. CONCLUSIONS: These findings indicate that PTEN loss coupled with PI3K/AKT/mTOR-mediated autophagy inhibition and apoptosis in DPCs is a key mechanism of stress-related hair loss induced by CRH and suggests that topical activation of PTEN or enhancement of autophagy, e.g. through rapamycin, may have a therapeutic effect on stress-induced hair loss disorders such as alopecia.

Animals↗

PubMed2025

The pathway of autophagy in the epigenetic landscape of Mycobacterium-host interactions.

Macroautophagy (autophagy) is an evolutionarily conserved process that degrades excess cytoplasmic components, such as protein aggregates and damaged organelles, by encapsulating them within double-membrane autophagosomes. These autophagosomes undergo distinct stages - initiation, phagophore nucleation, expansion, and closure - before fusing with lysosomes (or occasionally endosomes) for degradation and recycling. This process is regulated by ATG (autophagy related) proteins, which govern autophagosome formation and lysosomal fusion. Epigenetic modifications and transcription factors can regulate ATG gene expression in the nucleus. Autophagy also plays a key role in eliminating intracellular Mycobacterium tuberculosis (Mtb) through the lytic and antimicrobial activities of autolysosomes, which are more potent antimicrobial compartments than conventional phagosomes. Emerging evidence suggests that Mtb can modify the host epigenome and transcriptional machinery, significantly affecting the host immune response. This review explores the epigenetic regulation of autophagy during mycobacterium-host interactions. The interplay between epigenetic regulation and autophagy highlights a crucial aspect of host-pathogen interactions during Mtb infection. Understanding how Mtb manipulates the host epigenome to regulate autophagy could lead to the development of novel therapeutic strategies that enhance autophagic pathways or counteract Mtb's immune evasion tactics.Abbreviations: AM: Alveolar macrophages; ATG: autophagy related; DNMT: DNA methyltransferase; FOXO3: forkhead box O3; HAT: histone acetyltransferase; HDAC: histone deacetylase; MIR: microRNA; MTOR: mechanistic target of rapamycin kinase; Mtb: Mycobacterium tuberculosis; ROS: reactive oxygen species; SIRT: sirtuin; STPK: serine/threonine protein kinase.

Autophagy↗

PubMed2026

Canonical lymphocyte chemokine receptors CXCR3 and CXCR5 modulate neuronal autophagy.

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.

Journal Article↗

PubMed2025

Panduratin A Induces Autophagy Through AMPK Activation Independent of mTOR Inhibition and Restricts Mycobacterium tuberculosis in Host Macrophages.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health burden, especially with the increasing prevalence of drug-resistant strains. There is an urgent need for new therapeutics that act via alternative mechanisms. Autophagy, a vital cell-autonomous defense process, allows macrophages to degrade intracellular pathogens such as Mtb and has gained attention as a potential target for host-directed therapy. In this study, we conducted a high-content imaging screen of herb-derived compounds to identify autophagy inducers in RAW264.7 macrophages. Panduratin A (NPA), a natural compound from Boesenbergia rotunda, was found to potently induce autophagy. NPA promoted autophagic vacuole formation in a dose-dependent fashion at low micromolar levels. Its autophagy-inducing effect was validated using RFP-GFP-LC3 dual fluorescence assays and immunoblotting in the presence of bafilomycin A1. Further mechanistic analysis revealed that NPA activates autophagy through AMPK activation, independent of mTOR inhibition. Importantly, NPA significantly promoted intracellular Mtb clearance and increased colocalization of Mtb with autophagosomes and lysosomes, in a manner dependent on Beclin-1. These findings highlight NPA as a potent enhancer of macrophage antimicrobial responses via autophagy, supporting its potential as a candidate for host-directed adjunctive therapy against TB.

Autophagy↗

PubMed1992

Cellular autophagy in proximal tubules of early diabetic rats following insulin treatment and islet transplantation.

The influence of insulin treatment (group 1) and allogenic islet transplantation (group 2) on renal cellular autophagy were evaluated in adult Lewis rats in the early phase of streptozotocin-induced diabetes mellitus--a condition in which autophagy is inhibited and renal mass is increased. Three days after insulin treatment or islet transplantation (IT), the right kidney was resected and cortical tubular tissue was examined by quantitative electron microscopy. In group 1, the volume and numerical densities of autophagic vacuoles (AVs) increased by 70% and 80% respectively in the proximal tubular cells compared with saline-injected controls. The additive effect of unilateral nephrectomy (Ux) on cellular autophagy was investigated 1 or 2 days after Ux. Compared with the resected right kidney, the volume and numerical densities of AVs in the remnant left kidney decreased by 49% and 43% in the insulin-treated rats, and by 43% and 39% in the saline-injected diabetic animals. In group 2, the volume and numerical densities of AVs increased by 45% and 44% in parenchyma regressing from diabetic hypertrophy after IT, compared with sham-operated controls. After Ux, the volume and numerical densities of AVs decreased by 49% and 43% in IT rats, and by 41% and 53% in the still diabetic sham-operated animals. The data show that inhibition of cellular autophagy in the proximal tubules of the early diabetic kidney can be reversed by insulin replacement, despite the fact that insulin per se inhibits cellular autophagy in the nondiabetic kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2024

Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction.

LRRK2 polymorphisms (G2019S/N2081D) that increase susceptibility to Parkinson's disease and Crohn's disease (CD) lead to LRRK2 kinase hyperactivity and suppress autophagy. This connection suggests that LRRK2 kinase inhibition, a therapeutic strategy being explored for Parkinson's disease, may also benefit patients with CD. Paneth cell homeostasis is tightly regulated by autophagy, and their dysfunction is a precursor to gut inflammation in CD. Here, we found that patients with CD and mice carrying hyperactive LRRK2 polymorphisms developed Paneth cell dysfunction. We also found that LRRK2 kinase can be activated in the context of interactions between genes (genetic autophagy deficiency) and the environment (cigarette smoking). Unexpectedly, lamina propria immune cells were the main intestinal cell types that express LRRK2, instead of Paneth cells as previously suggested. We showed that LRRK2-mediated pro-inflammatory cytokine release from phagocytes impaired Paneth cell function, which was rescued by LRRK2 kinase inhibition through activation of autophagy. Together, these data suggest that LRRK2 kinase inhibitors maintain Paneth cell homeostasis by restoring autophagy and may represent a therapeutic strategy for CD.

Leucine-Rich Repeat Serine-Threonine Protein Kinas↗

PubMed2026

Crotonylome profiling identifies MLKL crotonylation in lupus nephritis associated with RAB1A-mTOR signalling and autophagy changes in tubular epithelial cells.

OBJECTIVE: To investigate whether MLKL crotonylation is associated with tubular autophagy-lysosome pathway homeostasis in lupus nephritis (LN) and to explore its relationship with RAB1A-mechanistic target of rapamycin (mTOR) signalling. METHODS: Crotonylome proteomics was performed in peripheral blood mononuclear cells from patients with LN, patients with systemic lupus erythematosus without nephritis and healthy controls. Renal biopsy tissues were evaluated for tubulointerstitial fibrosis and autophagy-lysosome pathway-related markers. Mechanistic studies were conducted in lipopolysaccharide-stimulated HK-2 cells. Autophagic flux was assessed using bafilomycin A1. The dependency of mTOR/autophagy changes on RAB1A was tested by siRNA-mediated knockdown. RESULTS: MLKL was identified as a differentially crotonylated protein in LN, with increased crotonylation at K95 and K219. Kidney tissues from patients with LN showed increased fibronectin and collagen III deposition compared with controls, whereas no significant difference was observed between class IV and class V LN. LC3 signal did not differ significantly between groups, whereas LAMP1 expression and LC3-LAMP1 co-localisation were reduced in LN. In HK-2 cells, crotonylation-deficient MLKL mutants were associated with increased LC3-II and reduced p62, whereas K219Q showed the opposite pattern. Autophagic flux assays using bafilomycin A1 showed that K219R-expressing cells had higher LC3-II levels than WT cells both before and after lysosomal inhibition, with comparable BafA1-induced LC3-II accumulation, consistent with increased autophagosome formation rather than impaired lysosomal degradation. HDAC1 knockdown increased MLKL crotonylation and was accompanied by mTOR activation. MLKL crotonylation enhanced RAB1A guanriphosphat osphate (GTP) binding without altering total RAB1A abundance. RAB1A knockdown in MLKL WT-expressing cells attenuated mTOR phosphorylation and partly reversed the autophagy-suppressive marker profile. Sodium crotonate induced an autophagy-suppressive marker profile that was partly reversed by rapamycin. CONCLUSION: MLKL crotonylation is associated with activation of the RAB1A-mTOR axis and altered tubular autophagy-lysosome pathway homeostasis in LN. These findings suggest that tubular injury-related changes in LN may not be fully reflected by glomerulus-based classification alone.

Humans↗

PubMed2026

CRISPR screen identifies autophagy inhibition (GNS561) as a PARP inhibitor (AZD5305) combination strategy in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is a deadly cancer with few treatment options and poor prognosis, creating a dire need for improving therapies. Poly (ADP-ribose) polymerase inhibitors (PARPi) have been tested as a treatment strategy, but patient response varies. We aimed to identify novel approaches to sensitize SCLC to PARPi through a genome-wide CRISPR dropout screen. METHODS: Genome-wide CRISPR dropout screening was conducted in two SCLC cell lines using the PARPi, olaparib, as the selection pressure. Stable shRNA-mediated knockdown cell lines were validated by Western blotting and tested for olaparib sensitivity by assaying for cell viability. Synergy between PARPi and autophagy inhibition was tested by treating SCLC cell lines and analyzing cell viability using SynergyFinder+. The therapeutic strategy combining AZD5305 (PARPi) and GNS561 (novel autophagy inhibitor) was tested in cell line-derived xenograft mouse models. RESULTS: CRISPR screening identified the loss of mTOR negative regulators as a mechanism of PARPi sensitivity in SCLC, and knockdown of TSC1 and TSC2 sensitized SCLC cell lines to olaparib. Therapeutic strategies combining PARPi and autophagy inhibition demonstrated synergy in SCLC cell lines, and combination therapy with AZD5305 and GNS561 was effective in cell line-derived xenograft mouse models. CONCLUSIONS: Autophagy inhibition downstream of the mTOR pathway is a mechanism of PARPi sensitivity in SCLC. This suggests that a therapeutic combination of autophagy inhibition and PARPi is a promising treatment strategy in SCLC, paving the way for the adoption of novel treatments in this disease context.

Autophagy↗

PubMed1977

Diurnal variation of autophagy in rod visual cells in the rat.

In the process of autophagy, parts of the cell's own cytoplasm are enclosed by membranes and subsequently digested by enzymes. Autophagy is a well-known process found in various tissues under different conditions (See Refs.). Autophagy in visual cells was first documented by Remé and Young (1977) and Remé (1977), and was considered to be a general and important degradative pathway in visual cell metabolism. Recently, La Vail (1976) demonstrated that the shedding of disks from the tips of rod outer segments followed a circadian rhythm in rats. The peak period of disk shedding occurred shortly after the onset of the lighting period. In this study we have demonstrated, by quantitative analysis, that autophagy in rod inner segments follows a diurnal variation. The peak period of autophagic activity occurs about 3 h after the peak period of disk-shedding. Both peak periods take place in daytime, when the animals are less active. This finding further supports our assumption of autophagy being an important pathway in visual cell degradative mechanisms.

Adaptation, Physiological↗

PubMed2025

NME2 modulates HCC progression through 4EBP1 phosphorylation and autophagy regulation independent of mTOR.

BACKGROUND: To investigate the role of nucleoside diphosphate kinase 2 (NME2) in HCC progression, assessing its therapeutic potential. METHODS: Utilizing transcriptome sequencing data from The Cancer Genome Atlas (TCGA) and immunohistochemical staining of tissue microarrays, we analyzed NME2 expression in HCC tumor tissues. The effects of NME2 on HCC cell proliferation and autophagy flux were assessed through knockdown and overexpression experiments. Additionally, the relationship between NME2 and 4EBP1 phosphorylation was explored through specific site mutation analysis. RESULTS: NME2 overexpression in HCC correlated with poor prognosis. NME2 knockdown significantly hindered HCC cell proliferation and induced autophagy flux. Notably, NME2 modulates 4EBP1 phosphorylation (Thr37/46) independently of mTOR, unveiling a novel axis in HCC pathogenesis. Additionally, NME2 modulates eukaryotic translation initiation factor 4F (eIF4F) complex formation and autophagy flux. CONCLUSIONS: NME2 plays a crucial role in HCC development by modulating 4EBP1 phosphorylation and autophagy through an mTOR-independent pathway. Our research underscores NME2's significance as a potential therapeutic target in HCC, meriting further exploration of its underlying mechanisms and clinical applicability.

Humans↗

PubMed1989

Neuronal autophagy in experimental Creutzfeldt-Jakob's disease.

We report an experimental model of Creutzfeldt-Jakob's disease (CJD) in mice leading to the formation of giant autophagic vacuoles (AV) in neurons of the cerebral cortex. These AV appear at the end of the incubation period (4-6 months postinoculation), together with spongy changes and clinical symptoms. Autophagy, a process of intracellular digestion of cell constituents by the lysosomal compartment, is known in many cell types, where it plays a role both in the physiological turnover and in pathological processes and is involved in protein metabolism. The same also occurs in neurons. Here autophagy is known to occur in the normal state and leads to residual bodies called lipofuscin granules. An increase in lipofuscin is known to occur in human and experimental CJD. Therefore, an increase in autophagy and in AV can be expected. In our experimental model, the activation of neuronal autophagy may be related to an alteration in neuronal protein metabolism.

Animals↗

PubMed2026

An SLC7A5-dependent nutrient-sensing circuit overcomes cisplatin tolerance via mTOR-autophagy signaling.

Cisplatin-based chemotherapy responses are highly heterogeneous across cancers, with the mechanisms governing drug sensitivity remaining incompletely understood. Using genome-wide CRISPR-Cas9 knockout screening, we systematically characterized regulators of cisplatin response and uncovered a counterintuitive finding: mTOR inhibition promotes cisplatin tolerance, contradicting the canonical view that PI3K-AKT-mTOR activation confers chemoresistance. Mechanistically, both mTOR suppression and cisplatin treatment converge to activate cytoprotective autophagy, which enhances cancer cell survival under therapeutic stress. The amino acid transporter SLC7A5 was identified and validated as a key integrator of the mTOR-autophagy axis that modulates cisplatin sensitivity. SLC7A5 expression positively correlates with cisplatin sensitivity across cancer cell lines, and its downregulation is associated with cisplatin resistance in multiple cancer types, supporting its potential as a mechanistically grounded predictive biomarker. Translationally, leucine supplementation sensitizes cancer cells to cisplatin in an SLC7A5-mTOR-autophagy-dependent manner. Collectively, our study defines a novel mTOR-autophagy adaptive loop governing cisplatin tolerance, positions SLC7A5 as a central regulatory node with both biomarker and therapeutic target value, and proposes leucine supplementation as a simple, translatable strategy to improve cisplatin efficacy in SLC7A5-expressing tumors.

Cisplatin↗