Piceatannol alleviates oxidative stress and ferroptosis in alcohol-induced liver injury by activation of Nrf2/GPX4 signaling.

Alcoholic liver disease (ALD) poses a significant global health burden and has limited therapeutic options. This study investigates the therapeutic efficacy of piceatannol (PIC) in mice with pre-existing ALD. In vivo, during the last 2 weeks of the 6-week ethanol model establishment process, PIC treatment was able to alleviate liver inflammation, oxidative stress and ferroptosis. In vitro, PIC pretreatment effectively counteracted ethanol-triggered ferroptosis and inflammatory cytokine release in hepatocytes, effects that were nullified by the nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML385. Mechanistically, PIC disrupted the Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 interaction, inhibiting Nrf2 ubiquitination and facilitating nuclear translocation to activate the downstream heme oxygenase-1 (HO-1) antioxidant pathway. These findings establish PIC as a novel modulator of the Keap1-Nrf2 axis, exerting dual antioxidant and anti-ferroptosis effects to ameliorate ALD progression. Our work highlights therapeutic targeting of the Nrf2 pathway for alcohol-associated hepatic damage.