TRIM16 mediates YAP1 K63-linked ubiquitination to alleviate sepsis-induced acute liver injury through YAP/Nrf2 axis in mice.

Sepsis-induced liver injury is associated with high morbidity and mortality, yet its underlying mechanisms remain elucidated. In this study, we observed a significant reduction in the E3 ubiquitin ligase TRIM16 in lipopolysaccharide (LPS)-injured hepatocytes; however, its functional role and regulatory mechanisms were unclear. Using in vitro LPS-induced hepatocyte injury and in vivo cecal ligation and puncture (CLP)-induced septic liver injury models, we investigated TRIM16's effects via small interfering RNA and AAV9-overexpression plasmids in hepatocytes. Results demonstrated that TRIM16 overexpression rescued LPS-induced suppression of hepatocyte viability, reduced cellular dysfunction (ALT, AST), and significantly suppressed pro-inflammatory cytokine expression (TNF-α, IL-6) and oxidative stress (SOD, MDA). Conversely, TRIM16 silencing exacerbated hepatocyte damage and dysfunction. In septic mice, TRIM16 overexpression alleviated liver injury and fibrosis by inhibiting oxidative stress and inflammatory responses. Mechanistically, TRIM16 directly bound to and stabilized YAP1 through K63-linked ubiquitination, facilitating its nuclear translocation. This process enhanced Nrf2 activation and subsequent expression of antioxidant genes. Collectively, our findings reveal that TRIM16 protects against septic liver injury by mitigating oxidative stress and inflammation via the YAP1/Nrf2 pathway, highlighting its potential as a therapeutic target for sepsis-induced acute liver injury.