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

TL;DR

Lactate promotes heart cell death through a specific protein interaction, worsening heart damage after blood flow is restored.

Contribution

The study reveals a novel mechanism where lactate-induced YTHDF2 lactylation promotes cardiomyocyte ferroptosis in myocardial ischemia-reperfusion injury.

Findings

Lactate levels increase in MI/R hearts, correlating with structural damage and elevated Fe²⁺ and CK-MB levels.

YTHDF2 lactylation by lactate reduces FTH1 mRNA stability, promoting ferroptosis in cardiomyocytes.

Knockdown of YTHDF2 suppresses ferroptosis, an effect reversed by FTH1 reduction.

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.

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

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