autophagy

Overview

Autophagy is a conserved intracellular catabolic process by which cells sequester cytoplasmic material, including damaged organelles and protein aggregates, into double-membrane vesicles for delivery to lysosomes for degradation and recycling. It is essential for maintaining cellular homeostasis, supporting adaptation to nutrient deprivation and other stresses, and regulating metabolism, inflammation, senescence, and cell survival. In biomedical research, autophagy is often discussed alongside autophagic flux, p62/SQSTM1 (Sequestosome 1), Microtubule associated protein 1 light chain 3 beta, BECN1, and Autophagy related 5, which are commonly used to assess or mechanistically interpret the pathway.

Functionally, autophagy is tightly connected to major signaling networks such as AMP-activated protein kinase alpha 1 (AMPKα1), Mechanistic target of rapamycin (mTOR), Protein kinase B (PKB), and BCL2 apoptosis regulator, and it intersects with oxidative stress, reactive oxygen species, inflammation, ferroptosis, and apoptosis. Depending on context, autophagy may promote cell survival by sustaining metabolism, or contribute to disease processes when dysregulated, including cancer, diabetic neuropathy, aging-related decline, and wound healing defects.

Recent Publications Summary

Recent studies establish autophagy as a key therapeutic target for tissue repair and organ protection through activation strategies. Isopsoralen promoted mandibular fracture healing in rats via autophagy upregulation, with autophagy inhibition by 3-methyladenine impairing the healing process 42596530Aug. In diabetic complications, exosomal delivery of miR-2467-3p from human umbilical cord mesenchymal stem cells enhanced wound healing by modulating autophagy through CYP1A1 targeting 42142644May. The traditional Chinese herbal formula Shenqi Oral Liquid protected against doxorubicin-induced chronic heart failure in mice by regulating autophagy and mitochondrial dynamics via the AMPK/mTOR signaling axis 41997434Apr. In neurodegenerative disease models, beauvericin promoted both autophagy and mitophagy via NIPSNAP2 activation, reducing amyloid-β levels through lysosomal degradation of BACE1 and ameliorating Alzheimer's disease-relevant cellular phenotypes 42044561Apr.

Conversely, autophagy inhibition emerged as an effective anticancer strategy across multiple malignancies. In pancreatic ductal adenocarcinoma, autophagy inhibition reprogrammed the tumor microenvironment by recruiting macrophages via the CXCL1/2-CXCR2 axis while decreasing CD47 expression on tumor cells, thereby promoting macrophage-mediated phagocytosis and antitumor immunity 42224631Jun. Combined inhibition of the amino acid transporter SLC6A14 and autophagy/macropinocytosis pathways significantly reduced pancreatic cancer cell viability and clonogenic potential compared to monotherapy 41952621Apr, demonstrating that autophagy-mediated nutrient scavenging sustains cancer cell survival under metabolic stress. In drug-resistant triple-negative breast cancer, nitroalkenes re-sensitized PARPi-resistant cells to poly-ADP ribose polymerase inhibitors by targeting the autophagy regulator p62 through cysteine alkylation, which impaired p62-mediated autophagy 41974247Apr. At the molecular level, the small molecule ATI-1 inhibited autophagy initiation by disrupting the VCP-UFL1-Beclin1 axis, triggering metabolic catastrophe in autophagy-dependent malignancies 42060985Apr.

Mechanistic investigations revealed autophagy dysregulation as a pathological driver in multiple disease contexts. Chronic hyperglycemia in diabetic neuropathy impaired autophagic flux, evidenced by decreased LC3I/II ratios and increased p62 accumulation, with dysregulation of key transcription factors (TFEB, FOXO3, NRF2) contributing to neuronal dysfunction and linked to lipid metabolism dysregulation 42424320Jul. Environmental pollutants such as bisphenol S induced cellular senescence in endometrial stromal cells, which was effectively attenuated by autophagy activation with rapamycin 42114668May. In ovarian aging, impaired autophagy emerged as a critical molecular mechanism alongside dysregulation of major longevity pathways including PI3K/AKT/mTOR, AMPK, and sirtuins 41833148Mar. These findings demonstrate that autophagy dysfunction serves as both a pathological driver and a therapeutic vulnerability across diverse tissues and disease states.

What Changes, What Holds

1. Autophagy activation improves tissue repair and organ protection across multiple pathologies
NEW DIRECTION Therapeutic autophagy activation improved tissue repair and organ function across multiple pathologies 42596530Aug41997434Apr. The Overview establishes that autophagy promotes survival but does not discuss autophagy activation as an intervention. These findings establish a therapeutic direction—targeted autophagy enhancement to correct dysfunction in tissues where dysregulation contributes to disease—extending the baseline's descriptive account to explicit interventional application.

2. Autophagy inhibition reprograms cancer immunity and reverses therapeutic resistance
NEW DIRECTION Autophagy inhibition recruited antitumor macrophages in pancreatic cancer and re-sensitized triple-negative breast cancer to PARP inhibitors 42224631Jun41974247Apr, demonstrating that blocking autophagy-mediated survival and nutrient scavenging attacks cancer across mechanisms and resistance states. The Overview identifies autophagy promotion of survival; these findings establish therapeutic autophagy inhibition as a distinct anticancer strategy not addressed in the baseline.

3. Dysregulation of core signaling nodes drives autophagy dysfunction across disease contexts
REINFORCES Impaired autophagic flux with dysregulation of TFEB, FOXO3, NRF2 in diabetic neuropathy 42424320Jul and dysregulation of PI3K/AKT/mTOR, AMPK, and sirtuins in ovarian aging 41833148Mar mechanistically elaborate the baseline's statement that autophagy dysfunction "contributes to disease processes" including "diabetic neuropathy" and "aging-related decline," while confirming the Overview's described connection to these signaling networks.

Overview update candidates: autophagy activation as therapeutic target for tissue repair (1); autophagy inhibition for cancer treatment (2); and dysregulation mechanisms in neuropathy and aging (3).