• Phillyrin alleviates myocardial ischemia/reperfusion injury by reducing apoptosis, oxidative stress, and inflammation in vitro and in vivo.
• Multiomics identifies KNL1 as a key target, with acetylation at K605 enhancing its protein stability and expression.
• Phillyrin promotes KNL1 K605 acetylation by enhancing interaction with acetyltransferase p300/CBP, leading to inhibition of the p53/p21 pathway.
• KNL1 K605 acetylation represents a novel posttranslational modification target for cardioprotection against MIRI.