乳酸介导的CLYBL乳酰化修饰调控压力负荷型慢性心力衰竭模型心肌纤维化的作用及机制OA

Objective Heart failure(HF)remains a major global health burden,with myocardial fibrosis and metabolic remodeling representing central pathological features.Protein lactylation,a recently identified post-translation-al modification,has been implicated in fibrotic processes across multiple diseases;however,its role in myocardial fibrosis remains unclear.This study aimed to elucidate the molecular mechanism by which elevated cardiac lactate promotes myo-cardial fibrosis through lactylation and to identify key lactylated proteins using high-throughput proteomic approaches.Methods Cardiac lactate levels and global protein lactylation were measured in pressure overload-induced chronic HF models in mice and pigs,compared with controls.In vitro,lactate levels in cardiac fibroblasts were manipulated to evalu-ate changes in protein lactylation and fibrosis-related markers.A porcine pressure overload-induced chronic HF model was established for large-animal validation.Lactylome profiling was performed to identify differentially lactylated pro-teins,followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment an-alyses to explore underlying mechanisms.Results Compared with controls,cardiac tissues from both murine and porcine HF models exhibited significantly elevated lactate levels(t=6.128,P＜0.001;t=3.941,P＜0.05)and global protein lactylation(t=9.857,P＜0.000 1;t=2.567,P＜0.05).Modulation of lactate concentration in cardiac fibroblasts in vitro led to corresponding changes in lactylation levels and expression of fibrosis-associated markers.Proteomic and lac-tylomic analyses of porcine myocardial tissue identified a markedly increased lactylation at the CLYBL_K58 site(log2 fold change＞6),representing the most prominently altered modification.GO and KEGG enrichment analyses indicated that differentially lactylated proteins were primarily involved in glucose and lipid metabolic pathways.Conclusion Elevated lactate levels in heart failure promote myocardial fibrosis by inducing protein lactylation and activating cardiac fibroblasts.Lactylome profiling identified CLYBL_K58 as a key lactylation site significantly altered during HF progression,suggesting that lactate-driven lactylation may represent a novel regulatory mechanism and potential therapeutic target in myocardial fibrosis.