2. Academic Validation
  3. Lactate regulates the YTHDF2-FTH1 axis to promote cardiomyocyte ferroptosis and aggravate myocardial ischemia-reperfusion injury

Lactate regulates the YTHDF2-FTH1 axis to promote cardiomyocyte ferroptosis and aggravate myocardial ischemia-reperfusion injury

  • Sci Rep. 2026 Jan 8;16(1):4865. doi: 10.1038/s41598-026-35130-3.
Zhonghao Xiang 1 2,  Bitao Xiang 1 2,  Tianyu Ouyang 1 2,  Yadong Long 3 4,  Chengliang Zhang 5 6
Affiliations

Affiliations

  • 1 Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, People's Republic of China.
  • 2 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
  • 3 Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, People's Republic of China. [email protected].
  • 4 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People's Republic of China. [email protected].
  • 5 Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan, People's Republic of China. [email protected].
  • 6 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People's Republic of China. [email protected].
PMID: 41507543 DOI: 10.1038/s41598-026-35130-3
Abstract

Myocardial ischemia–reperfusion (MI/R) injury remains a major clinical challenge, and Ferroptosis has recently emerged as a crucial contributor to its pathogenesis. However, the regulatory mechanisms underlying Ferroptosis in MI/R remain incompletely understood. Here, we investigated the role of lactate-mediated YTHDF2 regulation in cardiomyocyte Ferroptosis. A murine ischemia–reperfusion (I/R) model and an H9C2 hypoxia/reoxygenation (H/R) model were established. Biochemical assays revealed elevated lactate levels in MI/R hearts, accompanied by increased infarct size, enhanced structural damage, and elevated Fe²⁺ and creatine kinase-MB (CK-MB) levels. Lactate treatment promoted YTHDF2 lactylation and upregulated its expression in cardiomyocytes. Mechanistically, YTHDF2 bound to ferritin heavy chain 1 (FTH1) mRNA and reduced its stability through m6A-dependent degradation, thereby promoting Ferroptosis. Knockdown of YTHDF2 suppressed Ferroptosis, an effect reversed by FTH1 reduction. These findings identify lactate-induced YTHDF2 lactylation as a key driver of cardiomyocyte Ferroptosis and reveal a novel mechanism exacerbating MI/R injury, suggesting that targeting this pathway may represent a potential therapeutic strategy.

Supplementary Information: The online version contains supplementary material available at 10.1038/s41598-026-35130-3.

Keywords

FTH1; Ferroptosis; Lactylation; Myocardial ischemia-reperfusion injury; YTHDF2.

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