Insulin-activated β-cell-liver axis protects against acetaminophen-induced acute liver injury by suppressing oxidative stress and purine catabolism.

β-Cell-hepatocyte communication is vital for the pathogenesis of liver-related diseases, however, its role in acetaminophen (APAP)-induced acute liver injury (ALI) remains poorly understood. This study aimed to investigate the effect of insulin-mediated β-cell-liver crosstalk on APAP-induced ALI and its underlying mechanisms. Streptozotocin-induced β-cell destruction or postprandial insulin stimulation was used to modulate serum insulin levels in mice. As a result, insulin deficiency exacerbated APAP-induced liver injury and inflammation, whereas elevated insulin levels during the postprandial period attenuated APAP hepatotoxicity in mice. In vitro, insulin directly enhanced cell viability and suppressed apoptosis and reactive oxygen species (ROS) accumulation in HepG2 cells exposed to APAP. Additionally, insulin mitigated APAP-induced injury in primary hepatocytes, as evidenced by decreased transaminase liver damage markers in the supernatant. Mechanistically, insulin exerted hepatoprotective effects by inhibiting the ROS/MAPK pathway in a PI3K-AKT-dependent manner. Moreover, untargeted metabolomics analysis suggested that insulin also suppressed purine catabolism, which is linked to the PI3K-AKT signaling pathway. This study elucidates insulin-mediated cytoprotective mechanisms against APAP-induced ALI, revealing a novel pathogenesis of APAP-induced ALI through the β-cell-liver axis and suggesting that restoring hepatic insulin signaling or β-cell function could prevent APAP hepatotoxicity.