Autophagy is indispensable for maintaining hepatocyte integrity, metabolic homeostasis, and survival. While several autophagy-related proteins have been studied in hepatic physiology, the specific role of Autophagy Related 14 (ATG14) in liver health has remained unclear. A new study published in eGastroenterology provides compelling in vivo evidence that ATG14 is a critical defender against hepatic injury, operating by suppressing multiple regulated cell death pathways.
- ATG14 is indispensable for maintaining hepatocyte identity and survival
Even under normal dietary conditions, Atg14 HepKO mice developed severe hepatomegaly, with liver weight increasing nearly fivefold. ALT and AST surged markedly, confirming hepatocellular injury. Importantly, loss of ATG14 disrupted hepatocyte identity, shown by reduced HNF4α expression, and increased compensatory proliferation. These changes occurred alongside macrophage infiltration and early fibrosis, indicating a rapid transition from injury to inflammatory remodeling.
- Oxidative stress and mitochondrial dysfunction drive tissue damage
HepKO livers exhibited widespread oxidative stress, with increases in ROS, lipid peroxidation (4-HNE), and DNA damage markers (8-OHdG). Antioxidant gene expression, including Sod1/2/3 and catalase, was significantly reduced. Mitochondria showed severe structural abnormalities on electron microscopy, including elongated shape, disorganized cristae, and reduced expression of respiratory chain complexes I, III and V, revealing profound metabolic collapse.
- ATG14 prevents the activation of multiple regulated cell death pathways
A major discovery of this study is that ATG14 deficiency unleashes simultaneous activation of apoptosis, necroptosis, pyroptosis, and PANoptosis: (1) Apoptosis: Increased cleaved caspase-3 and upregulated Bax, Apaf1, and Ddit3. (2) Necroptosis: Elevated Ripk3 and Mlkl expression. (3) Pyroptosis: Marked increases in NLRP3, AIM2, GSDMD, GSDME, and cleaved IL-1β. (4) PANoptosis: Upregulation of core mediators such as ZBP1, RIPK1, IRF1, STAT1, and caspase-8.
Immunofluorescence demonstrated that pyroptosis markers were predominantly elevated in hepatocytes, while inflammasome components were mainly increased in macrophages, highlighting coordinated multicellular injury responses.
- Western diet accelerates inflammation and fibrosis
When exposed to a Western diet, Atg14 HepKO mice experienced profound worsening of: (1) hepatocyte injury; (2) macrophage infiltration; (3) TNF-α production; (4) NF-κB pathway activation; (5) collagen deposition and fibrosis markers (COL1, COL3, ACTA2, TIMP1).
Hydroxyproline levels tripled, indicating substantial extracellular matrix accumulation. Transcriptomic analysis confirmed major upregulation of inflammatory, fibrotic, and cell-death–related pathways, along with suppression of metabolic pathways such as fatty acid oxidation and oxidative phosphorylation.
- Mechanistic validation confirms an autophagy-dependent process
Knockdown of ATG14 in human hepatoma cells sensitised cells to nigericin-induced pyroptosis, with strong NLRP3 activation. siRNA-mediated knockdown of ATG5 or ATG7 produced similar cell death signatures, demonstrating that ATG14's effects largely stem from its core autophagy function. Strikingly, NRF2 knockdown mitigated autophagy-deficiency–induced cell death, indicating NRF2 as a central mediator linking autophagy impairment to cell death pathways.
- Implications for Liver Disease Research and Therapeutics
ATG14 emerges as a pivotal regulator of hepatocyte survival and a promising therapeutic target for preventing the progression of liver injury to fibrosis, as enhancing ATG14 activity or restoring hepatic autophagy could mitigate damage in disorders such as MASLD, alcoholic hepatitis, toxin-induced injury, and viral hepatitis. The wide spectrum of cell death pathways unleashed by ATG14 loss highlights that autophagy is fundamental not only to metabolism but also to maintaining hepatocyte identity, genomic stability, mitochondrial function, and inflammatory balance. As metabolic liver diseases continue to rise globally, unraveling how autophagy failure drives injury and fibrosis holds significant relevance for precision medicine, paving the way for new therapeutic strategies, biomarkers, and targeted combination treatments.
In conclusion, this study establishes ATG14 as a master protector against liver injury by restraining multiple inflammatory cell death pathways. The work provides comprehensive mechanistic insights into how autophagy deficiency destabilizes hepatocyte homeostasis, promotes inflammation, and accelerates fibrosis—emphasising the therapeutic promise of targeting autophagy pathways in chronic liver disease.
See the article:
Kim H-G, Huang M, Wang S, et al. Autophagy related 14 protects against liver injury by inhibiting multiple cell death pathways. eGastroenterology 2025;3:e100181. doi:10.1136/egastro-2025-100181
About eGastroenterology
eGastroenterology, a BMJ journal partnered with Gut and launched by leading scientists in gastroenterology and hepatology, has been indexed in the Web of Science Core Collection (ESCI), PubMed, DOAJ, Scopus, CAS, ROAD, and many other major international databases within just two years of its launch. The journal is expecting to receive its first Impact Factor in June 2026.
