ATP6V0d2 alleviates acute liver injury via promoting hepatocyte autophagy

Liver injury is the pathological basis of various liver diseases, and severe acute liver injury can progress to acute liver failure with a high mortality. Although continuous progress has been made over the past few decades, the molecular mechanism underlying the progress of acute liver injury is still unclear. ATP6V0d2, a subunit of the vacuolar ATPase (V-ATPase) complex, is implicated in organelle acidification and intracellular degradation processes. In this study, three liver injury datasets were analyzed to screen the differentially expressed genes (DEGs) and identify Atp6v0d2, which was initially downregulated, and then upregulated to slightly higher than normal levels in both hepatocytes (HCs) and liver tissues in carbon tetrachloride (CCl₄)-induced acute liver injury, with the most significant downregulation observed 24 h after CCl₄ injection. Moreover, hepatocyte-specific overexpression of ATP6V0d2 alleviated CCl₄, concanavalin A (ConA) and acetaminophen (APAP)-induced acute liver injury by promoting hepatocyte autophagy, while silencing ATP6V0d2 inhibited hepatocyte autophagy and aggravated liver injury in vivo. In addition, consistent with the results of gene enrichment analysis, in vitro data demonstrated that ATP6V0d2 promoted hepatocyte autophagy mainly via facilitating the formation of autophagosomes. In conclusion, our results demonstrated that ATP6V0d2 played a protective role in acute liver injury by facilitating hepatocyte autophagy, which may provide a theoretical basis for the treatment and prognosis of acute liver injury.