autophagy pathways

Overview

Autophagy pathways are conserved intracellular degradation and recycling systems by which cells sequester damaged organelles, misfolded proteins, and cytoplasmic cargo within double-membraned vesicles called autophagosomes, which subsequently fuse with lysosomes for enzymatic breakdown and nutrient recovery. The process is orchestrated by a hierarchical network of autophagy-related (ATG) proteins, with central regulatory control exerted through the mechanistic target of rapamycin kinase (mTOR) and its upstream modulators, most notably AMP-activated protein kinase (AMPK). Under nutrient-replete or anabolic conditions, mTOR suppresses autophagy initiation; conversely, energy stress, oxidative damage, endoplasmic reticulum (ER) stress, and immune signaling converge on AMPK/mTOR axis modulation to induce autophagic flux. Key molecular markers of autophagy induction include the lipidation of LC3B (microtubule-associated protein 1 light chain 3 beta) and upregulation of BECN1 (Beclin-1), while the scaffold protein SQSTM1 (p62) serves as a cargo receptor and flux reporter.

Beyond basal housekeeping, autophagy pathways occupy a functionally ambivalent position in disease biology. They protect cells from inflammatory injury, support immune surveillance, and extend organismal lifespan, yet are also co-opted by cancer cells to survive therapeutic stress, evade immune destruction, and resist drug-induced death. The convergence of autophagy on processes as diverse as bone homeostasis, neurodegeneration, peritoneal fibrosis, tumor immunology, and aging immunosenescence reflects the pathway's fundamental role as a cellular stress-response hub, making it one of the most intensively investigated targets in translational biomedical research.

Focus of Latest Publications

Inflammatory and Metabolic Protection

A notable line of investigation has explored how autophagy pathways protect cells from inflammatory injury via the AMPK/mTOR signaling axis. One study demonstrated that betulinic acid (BA) shields MC3T3-E1 osteoblasts from inflammatory damage in an osteoporosis context by reducing reactive oxygen species (ROS) production and inhibiting NLRP3 inflammasome activation through AMPK/mTOR-mediated autophagy induction — connecting autophagy directly to Age-related osteogenic failure and oxidative stress. Similarly, research on functional dyspepsia found that the traditional herbal preparation Jiawei YigongSan ameliorates gastric motility by modulating PI3K/Akt/mTOR signaling and autophagy flux, illustrating that the PI3K/Akt/mTOR cascade is a recurrent nexus linking autophagy to gastrointestinal physiology.

Peritoneal fibrosis research added another dimension: finerenone, a selective mineralocorticoid receptor antagonist, was found to attenuate peritoneal fibrosis by restoring disrupted autophagy flux in peritoneal mesothelial cells, suggesting that impaired autophagic clearance underlies fibrotic remodeling and that pharmacological restoration of flux is therapeutically actionable.

Longevity and Immunosenescence

Autophagy dysfunction has been positioned as a mechanistic driver of immune aging. A clinical pilot study of spermidine supplementation in healthy older adults linked impaired autophagy to immunosenescence and chronic low-grade inflammation, proposing that autophagy induction can partially restore vaccine responsiveness in aged immune systems. In yeast, methionine restriction was shown to extend lifespan by activating a non-nitrogen-starvation (NNS)-induced autophagy pathway through limiting methylation of protein phosphatase 2A, establishing a direct epigenetic-autophagy-longevity axis that operates independently of canonical nitrogen-starvation signaling via the GATOR1 complex. Intermittent theta-burst stimulation (iTBS) in a spinocerebellar ataxia mouse model (SCA3/MJD) also activated autophagy, significantly enhancing Beclin-1 and LC3B expression, and modulated neuroinflammation — implicating autophagy as a mediator of neuroprotection downstream of non-pharmacological brain stimulation.

Cancer Biology: Dual Roles in Survival and Resistance

Autophagy plays a paradoxical role in oncology, functioning as both a tumor suppressor and a survival mechanism depending on context. In Ewing sarcoma, autophagy was identified as a resistance mechanism that impairs the sensitivity of cancer cells to PARP inhibitors (PARPi), paralleling findings in other tumor types where autophagic flux dampens drug-induced cytotoxicity. Polyploid giant cancer cells (PGCCs), which arise under therapeutic stress and drive tumor recurrence, were found to depend critically on autophagy for survival, structural integrity, and motility — suggesting that targeting autophagy may disrupt PGCC-driven relapse in aggressive malignancies.

Diffuse large B-cell lymphoma (DLBCL) research revealed that BTG1, induced by histone deacetylase (HDAC) inhibitors, acts as a tumor suppressor that is both necessary and sufficient for HDAC inhibitor-induced cell cycle arrest and autophagy; BTG1 silencing attenuated these effects, with nuclear β-catenin positivity and MYC implicated in the regulatory network downstream. In bladder cancer, Icariside II triggered endoplasmic reticulum stress-mediated autophagy coupled with lysosomal dysfunction, suppressing tumor progression. Conversely, an autophagy-blocking strategy using a ConTICT (consecutive twisted intramolecular charge transfer) photothermal agent was shown to induce lysosomal structural disruption and block autophagy processes, positioning autophagy inhibition as a complementary photothermal therapy approach.

Immunotherapy and CAR-T Cell Engineering

A mechanistically rich study identified TMED4 as an endogenous suppressor of CD8+ T cell function and CAR-T cell efficacy in solid tumors. TMED4 deficiency hyperactivated the IRE1α–XBP1 unfolded protein response axis and induced autophagy flux in an IRE1α (encoded by ERN1)-dependent manner, linking ER stress-driven autophagy to enhanced antitumor immunity. This IRE1α-autophagy axis positions autophagy not merely as a cell-intrinsic survival program but as a modulator of immune effector function relevant to CAR-T cell therapy against solid tumors, with implications for targets including EGFR/SRC-mediated EMT, IFNG, and IL17A signaling in the tumor microenvironment.

An independent approach employed a resveratrol dimer nanoagent to induce suprathreshold autophagy in combination with sonodynamic therapy (SDT), triggering immunogenic cell death (ICD) to synergize with cancer immunotherapy in metastatic settings. This work extended the concept that controlled autophagy induction — above a functional threshold — can reprogram the immunological response to dying tumor cells, complementing checkpoint blockade approaches.

Infection-Associated Metastasis and Intracellular Bacteria

Autophagy was harnessed therapeutically in a nanoplatform strategy (HSO-OMDs) designed to eliminate intracellular bacteria and block bacteria-driven epithelial-mesenchymal transition (EMT), thereby inhibiting tumor metastasis. The platform enhanced autophagic flux by promoting autophagosome maturation, autophagosome-lysosome fusion, and lysosomal acidification in tumor cells, demonstrating that autophagy machinery can be pharmacologically tuned to resolve both infectious and pro-metastatic stimuli simultaneously.

Neurological and Vascular Applications

In ischemic stroke, multiple studies converged on autophagy as a node linking neuroprotection to vascular and metabolic signaling. electroacupuncture (EA) was found to promote angiogenesis and ameliorate dysregulated autophagy after ischemic stroke by modulating the ELAVL1/SIRT1/FOXO1 pathway, while platelet-rich plasma-primed bone marrow mesenchymal stem cell-derived exosomes suppressed neuronal apoptosis and autophagy through the miR-29a-3p/PTEN/PI3K/Akt/mTOR axis following spinal cord injury. Separately, transcranial direct current stimulation (tDCS) attenuated stroke-induced autonomic and behavioral dysfunction via a renin-angiotensin system (RAS)-autophagy-iron axis in the brainstem, indicating that autophagy intersects with iron metabolism and the renin–angiotensin system in post-stroke pathophysiology.

Hematological and Autoimmune Contexts

Multiomics analysis of red blood cells in thalassemia revealed suppressed autophagy alongside elevated ferroptosis markers (ferritin heavy chain 1, ferritin light chain, heme oxygenase-1) and reduced cytoskeletal protein expression, pointing to autophagic insufficiency as a contributor to disease severity beyond globin gene mutations. In autoimmune hepatitis, naringin treatment in a ConA-induced mouse model modulated gut microbiota and Metabolites, with integrated multi-omics revealing significant alterations in MAPK, NF-κB, JAK-STAT, and autophagy pathways as downstream mediators of hepatoprotection.

Key Publications

• Jun EVs-MSC alleviate RA progression via USP21-dependent BRD2 stabilization to regulate autophagy in FLS. (Biochemical pharmacology, 2026, PMID 42302977): "Loss of USP21 disrupts autophagy balance, increasing LC3-II/Beclin1 while reducing p62, whereas EVs-MSC restore homeostasis."
• Jun Ginsenosides in Liver Fibrosis: Pharmacological Actions and Therapeutic Potential. (The American journal of Chinese medicine, 2026, PMID 42297734): "Furthermore, ginsenosides also influence cell fate-related processes, including autophagy and ferroptosis, in a cell-type-dependent manner."
• Jun Adipose stem cells-derived microvesicles and chicken egg-derived exosomes attenuate cardiac ischemia/reperfusion injury through AKT/ERK/Nrf2/HO-1 axis to inhibit apoptosis and inflammation and restore autophagy. (Life sciences, 2026, PMID 41921658): "...to inhibit apoptosis and inflammation and restore autophagy."
• Jun FTO Regulates Autophagy and Energy Metabolism in Sepsis-Induced Cardiomyopathy: Insights From Integrated Transcriptome and Proteome Analysis. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 42216755): "Multi-omics analysis of FTO-overexpressing cells revealed enrichment of autophagy and energy metabolism pathways."
• Jun Targeting TMED4 enhances CD8+ T cell function and CAR T cell efficacy in solid tumors through the IRE1α-autophagy axis. (Science advances, 2026, PMID 42284413): "Mechanistically, Tmed4 deficiency hyperactivated the inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) axis and induced autophagy flux in an IRE1α-dependent manner."
• Jun A resveratrol dimer nanoagent boosts sonodynamic-immunotherapy via suprathreshold autophagy. (Journal of controlled release : official journal of the Controlled Release Society, 2026, PMID 41871781): "Importantly, this nanoagent can not only address various limitations of SDT in modulating autophagy but also provide a novel metastatic cancer immunotherapy based on SDT and SA-induced ICD."
• Jun Autophagy-Enhanced Nanoplatforms Eliminate Intracellular Bacteria and Block Bacteria-Driven Epithelial-Mesenchymal Transition for Tumor Metastasis Inhibition. (ACS nano, 2026, PMID 42157648): "HSO-OMDs enhance autophagy by promoting the maturation of autophagosome, the fusion of autophagosomes and lysosomes, and the acidification of lysosomes in tumor cells."
• Jun BTG1 Acts as a Critical Tumor Suppressor Link Between HDAC Inhibition and β-Catenin Signaling Suppression in Diffuse Large B-Cell Lymphoma. (Molecular carcinogenesis, 2026, PMID 41950351): "Increased BTG1 expression was found to be both necessary and sufficient for HDAC inhibitor-induced cell cycle arrest and autophagy, whereas BTG1 silencing attenuated these effects."
• Jun Precise Modulation of Excited-State Energy Flow via Consecutive Twisted Intramolecular Charge Transfer (ConTICT) for Autophagy-Blocking Photothermal Therapy. (Angewandte Chemie (International ed. in English), 2026, PMID 41992636): "Furthermore, it induces disruption of lysosomal structures, and blocks autophagy processes."
• Jun Methionine Restriction Extends Yeast Lifespan by Activating Non-Nitrogen-Starvation-Induced Autophagy Through Limiting Methylation of Protein Phosphatase 2A. (Aging cell, 2026, PMID 42160763): "showing the critical role of the NNS-induced autophagy pathway in lifespan extension by MR."