Friedelin and 6-methoxyflavone from Imperata cylindrica ameliorate APAP-induced liver injury by activating AKT1 to suppress Caspase-3/GSDME-mediated pyroptosis.

Acetaminophen (APAP) overdose causes acute liver injury (ALI) by triggering regulated hepatocyte death. While Imperata cylindrica (Imperatae Rhizoma) (IR) is used in traditional medicine for its hepatoprotective effects, its active compounds and their capacity to modulate this pyroptotic switch remain unknown. In the present study, friedelin (FRI) and 6-methoxyflavone (6-METH) were identified as the principal active compounds of IR, and their protective effects against APAP-induced ALI were evaluated in vivo and in vitro. The results showed that both FRI and 6-METH significantly ameliorated APAP-induced liver injury and reduced hepatocyte death. Mechanistically, their hepatoprotective effects were associated with AKT1-dependent activation of the PI3K/AKT pathway, accompanied by suppression of Caspase-3/Gasdermin E (GSDME) signaling and attenuation of apoptosis and pyroptosis. Moreover, pharmacological inhibition or genetic silencing of AKT1 markedly weakened these protective effects. Taken together, these findings suggest that FRI and 6-METH are major hepatoprotective constituents of IR and that modulation of the AKT1-mediated Caspase-3/GSDME pathway may contribute to their protective actions against APAP-induced ALI. These findings validate its active compounds as promising therapeutic leads for ALI.