ArticleMolecular biology reports2026
Site-specific promoter hypermethylation of GPX4 in heart failure with reduced ejection fraction (HFrEF): nonlinear dose-response with hepatic and coagulation markers.
Article in Molecular biology reports, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
objectiveHeart failure with reduced ejection fraction (HFrEF) remains a major global health burden characterized by progressive cardiac dysfunction and high mortality. Emerging evidence suggests that epigenetic modifications, especially DNA methylation of antioxidant-related genes, may influence the molecular mechanisms underlying heart failure. This study aimed to investigate the methylation status of the glutathione peroxidase 4 (GPX4) promoter region in patients with HFrEF and to explore its associations with clinical and biochemical indicators.
methodsA total of 125 patients with HFrEF (LVEF < 50%) and 350 healthy controls were enrolled. Peripheral blood genomic DNA was extracted, and CpG methylation levels within the GPX4 promoter (FA3 and FA20 regions) were quantified using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS). Statistical analyses were performed using t-tests, Mann-Whitney U tests, and χ² tests. Restricted cubic spline (RCS) models were then applied to assess potential nonlinear dose-response relationships between methylation levels and clinical variables.
resultsMethylation at GPX4_FA3_CpG_5 was significantly higher in HFrEF patients than in healthy controls (P = 0.019). Stratified analysis by NYHA class revealed increased methylation at GPX4_FA20_CpG_6 in patients with class I/II heart failure compared with those with class III/IV disease (P = 0.017). RCS modeling identified nonlinear U-shaped or multiphasic associations between GPX4_FA3_CpG_5 methylation and several clinical indicators, including total bile acid (TBA), fibrinogen (FG), fibrin degradation products (FDP), and eosinophil percentage (EO%). No significant associations were detected between GPX4 methylation and blood lipid or routine hematologic parameters.
conclusionIn HFrEF patients, GPX4 promoter methylation is closely associated with clinical and biochemical alterations. Site-specific changes suggest that dysregulation of the GPX4-mediated antioxidant network and ferroptosis-related pathways may contribute to cardiac dysfunction. The nonlinear dose-response relationships with hepatic and coagulation markers indicate complex metabolic interplay. These findings support GPX4 promoter methylation as a potential epigenetic marker for HFrEF.
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