WTAP Histone Lactylation Drives the YTHDF1/ALOX15 Axis to Regulate Ferroptosis in Myocardial Ischemia-Reperfusion Injury

作者：Liu W, Wang Y, Wu J, He C, Zhou Z · 发表于：FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 年份：2026 · DOI：10.1096/fj.202600681RR · 被引用次数：41 · 研究领域：Myocardial Reperfusion Injury、Ferroptosis、Histones、Cell Cycle Proteins、RNA Splicing Factors、RNA-Binding Proteins、Animals、Rats、Myocytes, Cardiac、Rats, Sprague-Dawley、Male

Lactate, a metabolic byproduct of glycolysis, accumulates during myocardial infarction and ischemia/reperfusion (I/R) injury, acting as both a metabolic stress marker and a signaling molecule that influences inflammation and cell fate. Lactate can induce histone lysine lactylation (Kla), a novel post-translational modification that regulates gene transcription and immune responses. Despite this discovery, its role in I/R injury remains unclear. To investigate the effects of lactate and histone lactylation, both in vivo myocardial I/R injury and in vitro hypoxia/reoxygenation (H/R) injury models using cardiomyocytes were established. Lipid peroxidation, LDH, MDA, SOD, and iron levels were quantified using specialized fluorescent probes and commercial kits. MeRIP and RIP assays were performed to investigate WTAP, YTHDF1, and ALOX15 interactions. TEM was utilized to examine mitochondrial ultrastructure and morphology. Lactate levels were elevated in I/R rats, and reducing lactate levels effectively mitigated ferroptosis and myocardial injury. Furthermore, lactate promoted Kla of WTAP, resulting in upregulation of WTAP protein expression compared to the I/R group. Global m6A RNA methylation levels increased by lactate treatment. Elevated WTAP levels, or overexpression of YTHDF1, facilitated m6A modification of ALOX15 mRNA, leading to upregulation of ALOX15 expression and enhanced ferroptosis during I/R injury. Notably, overexpression of ALOX15 reversed the protective effects of W...