Exogenous melatonin alleviates liver injury via regulating hepatocellular PI3K/AKT pathway and inhibiting NLRP3 activation.

Melatonin (MT), a neurohormone secreted by the mammalian pineal gland, has been demonstrated to exert hepatoprotective effects. In this study, we employed exogenous MT intervention in both in vivo and in vitro models of chronic liver injury induced by D-galactose (D-gal) in mice to investigate the specific mechanisms underlying its hepatoprotective action, aiming to provide a reference for the prevention of liver injury by MT. Preliminary network toxicology and network pharmacology analyses revealed that D-gal possesses potential hepatotoxicity, whereas MT exerts hepatoprotective effects through modulating oxidative damage and inflammation. Further analysis indicated that the targets of MT and D-gal are highly enriched in the PI3K/AKT signaling pathway. We therefore examined the PI3K/AKT pathway and downstream proteins associated with NLRP3 inflammasome activation. Our results demonstrated that exogenous MT improves hepatic physiological function and alleviates liver injury by activating the PI3K/AKT signaling pathway, which in turn inhibits NLRP3 inflammasome activation.