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

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

  • Nat Commun. 2026 Mar 26;17(1):4442. doi: 10.1038/s41467-026-71108-5.
Huashan Liu # 1 2 3,  Ze Li # 1 2 3,  Dongxu Lei # 1 2 3,  Hao Xie # 1 2 3,  Xuanhua Yang 1 2 3,  Chi Zhou 4,  Shujuan Li 5,  Wenxin Li 6 7 8,  Ziwei Zeng 9 10 11,  Liang Kang 12 13 14
Affiliations

Affiliations

  • 1 Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3 Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 4 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 5 Department of Pharmacy, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 6 Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 7 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 8 Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 9 Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 10 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 11 Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 12 Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 13 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 14 Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41888123 DOI: 10.1038/s41467-026-71108-5
Abstract

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.

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