7,8-Dihydroxyflavone protects acetaminophen induced liver injury through activating PI3K/Akt/NRF2/GPX4 mediated ferroptosis suppression.

Acetaminophen (APAP)-induced liver injury remains a leading cause of acute liver failure, with limited therapeutic options beyond the narrow therapeutic window of N-acetylcysteine. Emerging evidence highlights ferroptosis as a critical mediator of APAP hepatotoxicity. Here, we investigated the hepatoprotective effects of 7,8-dihydroxyflavone (7,8-DHF), a natural flavonoid with antioxidative properties, against APAP-induced liver injury and explored its underlying mechanisms. In a murine model of APAP overdose, 7,8-DHF administration significantly attenuated liver damage, as evidenced by reduced serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, preserved histological integrity, and suppressed oxidative stress, evidenced by a rescue of APAP-induced 4-hydroxynonenal and malondialdehyde level. Transcriptomic analyses revealed that 7,8-DHF reversed APAP-induced dysregulation of lipid metabolism and reactive oxygen species (ROS) pathways. Mechanistically, 7,8-DHF promoted nuclear translocation of NRF2, upregulated GPX4 and SLC7A11 expression, and inhibited ferroptosis-associated factors (PTGS2, ACSL4). Pharmacological inhibition of PI3K/Akt or NRF2 abrogated 7,8-DHF-mediated ferroptosis suppression and hepatoprotection in vitro and in vivo. Collectively, our findings identify 7,8-DHF as a promising therapeutic agent for APAP-induced liver injury through modulation of the PI3K/Akt/NRF2/GPX4 axis, offering a novel strategy to target ferroptosis in drug-induced liver injury.