2'-Hydroxycinnamaldehyde mitigates acetaminophen-induced acute liver injury by inhibiting the Warburg effect-mediated pyroptosis via the PKM2-NLRP3 axis

[Display omitted] •2'-Hydroxycinnamaldehyde alleviates APAP-induced ALI.•2'-Hydroxycinnamaldehyde inhibits aerobic glycolysis and pyroptosis during APAP-induced ALI.•2'-Hydroxycinnamaldehyde prevents activation of NLRP3 inflammsome in APAP-induced ALI by inhibiting phosphorylation and nuclear translocation of PKM2.•2'-Hydroxycinnamaldehyde attenuates APAP-induced ALI activated pyroptosis by inhibiting the PKM2-NLRP3 axis via the Akt-mTOR signaling pathway.•2'-Hydroxycinnamaldehyde may serve as a potencial drug for the clinical treatment of APAP overdose. Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver injury. However, the underlying mechanisms appear to be multifaceted and there are few effective treatments. In this study, we used the 2'-Hydroxycinnamaldehyde (HCA), an active ingredient extracted from cinnamon stem bark to evaluate the therapeutic effect against APAP-induced ALI. The results indicated that pyruvate kinase M2 (PKM2)-mediated aerobic glycolysis may activate NLRP3 inflammasome in APAP-induced ALI, However, this process was prevented by HCA. Additionally, overexpression of PKM2 by adeno-associated virus (AAV9-PKM2) in vivo and plasmid (PKM2-OE) in vitro reversed the inhibition of NLRP3 inflammasome by HCA. Intriguingly, the HCA-triggered repressive pyroptosis was mediated through dephosphorylation and nuclear translocation of PKM2. Furthermore, the therapeutic effect of HCA on APAP-induced ALI was achieved by partially stimulating the Akt-mTOR signaling pathway, thus inhibiting the PKM2-NLRP3 axis. These findings elucidate that a potential drug to the clinical treatment of APAP overdose by HCA.