Coixol, a benzoxazolinone derived from coix seed, ameliorates disordered hepatocellular programmed responses in alcoholic-associated liver disease

Coixol, a benzoxazolinone from Coix seeds, exhibits anti-inflammatory and hepatoprotective effects. This study investigated its protection against alcohol-associated liver disease (ALD) and mechanisms. Twenty-four male C57BL/6 mice were randomly allocated into four groups (n = 6): Control, EtOH, EtOH + Coixol (25 or 50 mg/kg, oral gavage). In vitro, primary mouse hepatocytes were treated with EtOH ± Coixol (25 or 50 μM). In vivo and in vitro, SIRT6 and programmed responses (pyroptosis, apoptosis, necroptosis) were involved in EtOH-induced injury. Coixol significantly reduced serum ALT (216.2 ± 40.21 to 98.6 ± 25.5 U/L), AST (210.1 ± 41.65 to 91.6 ± 18.19 U/L), and TG (4.3 ± 0.41 to 0.9 ± 0.25 mmol/L), ameliorated histopathology and lipid accumulation. Mechanistically, Coixol upregulated SIRT6, downregulated pyroptosis (NLRP3, GSDMD, caspase-1, IL-1β), apoptosis (caspase-3, -9, BCL-2/Bax), necroptosis (P-MLKL/MLKL), and inhibited NETosis. SIRT6 deficiency attenuated Coixol's protection in EtOH-activated hepatocytes. Collectively, Coixol alleviates ALD via SIRT6-dependent regulation of programmed responses, supporting its therapeutic potential.