Bioorganic chemistry · 2025
Gentisic acid inhibits renal fibrosis by reprogramming glycolytic metabolism and regulating H3K18la.
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Wang Weili, Chen Yizhen, Cheng Meng, Wei Liuting, Sang Yonghao, Gao Yilin, Zhang Wei, Zhang Lei, Wang Yiping, Dai Rong
Аннотация
BACKGROUND AND AIM: Renal fibrosis, a hallmark of chronic kidney disease, is characterized by enhanced glycolysis and lactate accumulation. As a precursor of histone lactylation modification, lactate may be involved in the progression of renal fibrosis. Our previous studies found that gentisic acid (GA) can alleviate renal fibrosis, but its specific mechanism of action remains unclear. This study aimed to determine whether GA exerts an inhibitory effect on renal fibrosis by reprogramming glycolytic metabolism and regulating histone lactylation.
EXPERIMENTAL PROCEDURE: We employed Western blot, real-time quantitative polymerase chain reaction (RT-qPCR), RNA sequencing (RNA-seq), liquid chromatography-tandem mass spectrometry (LC-MS/MS), chromatin immunoprecipitation-qPCR (ChIP-qPCR), and immunofluorescence staining to investigate the effects and molecular mechanisms of GA on renal fibrosis in unilateral ureteral obstruction (UUO) mouse models and TGF-β1-induced Human kidney-2 proximal tubule epithelial cells (HK-2 cells).
KEY RESULTS: GA demonstrated significant anti-fibrotic effects both in vivo and in vitro. Multi-omics analysis (transcriptomics and metabolomics) revealed that the glycolytic pathway is a primary target of GA's anti-fibrotic action. Mechanistic studies further confirmed that GA inhibits lactate production and histone H3K18 lactylation (H3K18la) by regulating the glycolytic pathway, thereby suppressing the progression of renal fibrosis.
CONCLUSIONS AND IMPLICATIONS: This study is the first to demonstrate that GA has anti-fibrotic effects by influencing the glycolytic pathway. GA regulates the lactylation of histone H3 at the H3K18la locus, with lactate acting as a metabolic cue. Thus, H3K18la is a key link in GA's anti-renal fibrosis action, offering new insights for development anti-fibrotic drugs.
EXPERIMENTAL PROCEDURE: We employed Western blot, real-time quantitative polymerase chain reaction (RT-qPCR), RNA sequencing (RNA-seq), liquid chromatography-tandem mass spectrometry (LC-MS/MS), chromatin immunoprecipitation-qPCR (ChIP-qPCR), and immunofluorescence staining to investigate the effects and molecular mechanisms of GA on renal fibrosis in unilateral ureteral obstruction (UUO) mouse models and TGF-β1-induced Human kidney-2 proximal tubule epithelial cells (HK-2 cells).
KEY RESULTS: GA demonstrated significant anti-fibrotic effects both in vivo and in vitro. Multi-omics analysis (transcriptomics and metabolomics) revealed that the glycolytic pathway is a primary target of GA's anti-fibrotic action. Mechanistic studies further confirmed that GA inhibits lactate production and histone H3K18 lactylation (H3K18la) by regulating the glycolytic pathway, thereby suppressing the progression of renal fibrosis.
CONCLUSIONS AND IMPLICATIONS: This study is the first to demonstrate that GA has anti-fibrotic effects by influencing the glycolytic pathway. GA regulates the lactylation of histone H3 at the H3K18la locus, with lactate acting as a metabolic cue. Thus, H3K18la is a key link in GA's anti-renal fibrosis action, offering new insights for development anti-fibrotic drugs.