12-HEPE promotes cardiomyocyte proliferation by activating glycolysis and histone lactylation via Hippo signaling

Han Zhang; Zehao Feng; Kaixuan Tang; Li Zhang; Zhaohui Qiu; Lingmei Qian

doi:10.1016/j.ejphar.2025.177880

12-HEPE promotes cardiomyocyte proliferation by activating glycolysis and histone lactylation via Hippo signaling

Eur J Pharmacol. 2025 Jun 26:177880. doi: 10.1016/j.ejphar.2025.177880. Online ahead of print.

Authors

Han Zhang¹, Zehao Feng¹, Kaixuan Tang¹, Li Zhang², Zhaohui Qiu³, Lingmei Qian⁴

Affiliations

¹ Department of Cardiology & Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xianxia Road, Shanghai, 200336, China.
² Department of Cardiology & Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xianxia Road, Shanghai, 200336, China. Electronic address: li_zhang2019@126.com.
³ Department of Cardiology & Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xianxia Road, Shanghai, 200336, China. Electronic address: qzh3503@shtrhospital.com.
⁴ Department of Cardiology & Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xianxia Road, Shanghai, 200336, China. Electronic address: lmqian@shsmu.edu.cn.

PMID: 40581280
DOI: 10.1016/j.ejphar.2025.177880

Abstract

The regenerative capacity of the adult mammalian heart is limited, while neonatal hearts exhibit regenerative potential during the first postnatal week, driven by cardiomyocyte (CM) proliferation. This capacity declines with metabolic shifts, but the role of metabolites in CM proliferation remains unclear. Using LC-MS/MS, we identified lower levels of 12-HEPE, an omega-3 fatty acid metabolite, in postnatal day 7 (P7) and compared to postnatal day 1 (P1) mouse hearts. Supplementation of 12-HEPE has a positive effect on CM proliferation both in vivo and in vitro. Mechanistically, 12-HEPE activates the Hippo pathway to enhance CM glycolysis, thereby promoting CM proliferation. Moreover, 12-HEPE regulates the cell cycle by modulating H3K18la lactylation. These results suggest 12-HEPE as a key pro-proliferative metabolite and a potential therapeutic target for heart regeneration.

Keywords: 12-HEPE; cardiomyocyte proliferation; glycolysis.