Lactylation at lysine 145 fosters KAT8-TIP60 complex formation to promote p53 acetylation at lysine 120 and its pro-apoptotic function

p53 is crucial for cellular functions and disease mechanisms, yet effective clinical strategies targeting it remain challenging. Lactylation has emerged as a key factor in understanding disease pathology and offering therapeutic options. Herein, we identify lactylated KAT8 at lysine 145 (K145) as a modulator of p53 activity. GCN5 and SIRT6 function as the acyltransferase and delactylase for KAT8, respectively. K145 lactylation fosters the formation of KAT8-TIP60 complex, which couples with p53 to facilitate its acetylation at lysine 120 (K120). The KAT8-TIP60 complex promotes K120-acetylated p53 binding to the BAX and PUMA promoters, activating their transcription. Furthermore, we link KAT8 lactylation to doxorubicin-induced cardiotoxicity (DIC), showing that doxorubicin increases K145 lactylation, amplifying p53’s pro-apoptotic function and triggering cardiomyocyte apoptosis. Glimepiride, a therapeutic agent for type 2 diabetes, could target KAT8, disrupt its interaction with GCN5, inhibit KAT8 K145 lactylation, and mitigate DIC. These findings provide insight into how KAT8 K145 lactylation modulates p53 activity and contributes to DIC. The authors identify a KAT8 K145 lactylation switch that enhances TIP60 dependent p53 K120 acetylation and proapoptotic transcription, implicating this axis in doxorubicin cardiotoxicity and its mitigation by glimepiride.