KDM5B drives acute liver injury by impairing autophagy and activating cGAS-STING signaling via binding to ATG16L1

Abstract Acute liver injury (ALI) is a severe hepatic disorder characterized by high morbidity and mortality, presenting major challenges for clinical management. However, its underlying pathogenesis remains incompletely understood. Through analysis of four Gene Expression Omnibus (GEO) datasets using the Robust Rank Aggregation (RRA) method and RNA sequencing, the histone demethylase KDM5B was identified as a core upregulated gene in ALI. This finding was validated in carbon tetrachloride (CCl₄)-induced murine ALI models, in which KDM5B expression was significantly elevated. Liver-specific knockdown of KDM5B via AAV-shKDM5B alleviated hepatic injury by reducing immune cell infiltration and inflammatory cytokine release, while enhancing autophagic flux. Mechanistically, KDM5B bound to the autophagy-related protein ATG16L1, disrupting the assembly of the ATG12-ATG5-ATG16L1 complex and impairing autophagosome maturation. This led to the accumulation of cytoplasmic DNA, which activated the cGAS-STING-TBK1-IRF3/NF-κB signaling pathway and amplified pro-inflammatory responses. This study revealed a protein-interaction-dependent mechanism by which KDM5B inhibited autophagy and triggered cGAS-STING signaling. It uncovered a novel mechanism underlying the vicious cycle of impaired autophagy and excessive inflammation in ALI, offering a molecular basis and potential therapeutic target involving the KDM5B-ATG16L1 axis.