• Phillyrin attenuates myocardial ischemia/reperfusion injury by reducing apoptosis, oxidative stress, and inflammation in vitro and in vivo.
• Multiomics analysis identifies KNL1 as a key target, with phillyrin promoting its acetylation at K605.
• Phillyrin enhances KNL1-p300/CBP interaction, leading to KNL1 stabilization and inhibition of the p53/p21 pathway.
• Knockdown of Knl1 abolishes the cardioprotective effects of phillyrin, confirming the mechanistic dependence on KNL1.