YAP ameliorates CCl4-induced acute liver injury by activating autophagy via modulating p300/CBP-mediated FoxO3 acetylation

Carbon tetrachloride (CCl₄) induces hepatocyte necroptosis and perturbs local and systemic immunity, driving Acute Liver Injury (ALI). Yes-associated protein (YAP), a transcriptional coactivator orchestrating cell survival, differentiation and metabolism, critically regulates hepatocyte fate across diverse disease contexts. However, the regulatory mechanisms of YAP in carbon tetrachloride (CCl₄)-induced ALI remain to be fully elucidated. In the present study, we report that receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis was activated along with endogenous hepatic YAP after the CCl₄ challenge. Notably, pretreatment with a YAP inhibitor prior to CCl₄ challenge exacerbated hepatic injury, concomitant with enhanced necroptosis and impaired autophagic flux. Conversely, pharmacological activation of hepatic YAP attenuated acute liver injury (ALI) by restoring autophagy. In vitro studies revealed that YAP competitively recruits p300/CBP, thereby reducing p300/CBP-mediated acetylation of FoxO3 and enhancing FoxO3-dependent transcription of autophagy-related genes. In vivo, using FoxO3-knockdown mice (established via FoxO3-specific shRNA plasmid), we demonstrated that YAP confers hepatoprotection against CCl₄-induced toxicity primarily through FoxO3-dependent autophagy activation. Our work not only demonstrates that YAP holds promise as a novel therapeutic target for ALI, but also identifies MA-5 as a promising pharmacological candidate for mitigating ALI.