Salidroside alleviates doxorubicin-induced hepatotoxicity via Sestrin2/AMPK-mediated pyroptotic inhibition

Doxorubicin (DOX) is a potent anticancer drug, while its toxic side effects involve multi-organ toxicity, including hepatotoxicity. This study aims to investigate the therapeutic potential of salidroside against DOX-induced hepatotoxicity and elucidate its underlying mechanisms. Result showed that salidroside exhibited a liver protective effect in DOX-induced hepatotoxicity in mice, represented by the decreased serum ALT, AST and LDH levels, as well as the rescue of pathological changes in mice livers. Further study showed salidroside reduced the expression level of pyroptosis-associated proteins, including NLRP3, cleaved-caspase 1, gasdermin D (GSDMD-N) and mature IL-1β in mice liver tissues. In vitro study confirmed salidroside exerted a similar effect in AML12 cells. Mechanistically, salidroside alleviated mitochondrial dysfunction by activating the PGC-1α/Mfn2 signaling pathway, and restrained the endoplasmic reticulum (ER) stress, represented by the downregulation of GRP78 and p-PERK/PERK level. Subsequent investigations revealed that salidroside activated the Sestrin2/AMPK pathway, while the application of AMPK inhibitors, PGC-1α siRNA or Sestrain2 siRNA reversed the effects of salidroside on ameliorating mitochondrial dysfunction and ER stress, suggesting salidroside could be a promising therapeutic strategy for alleviating DOX-induced hepatotoxicity.