Lactylation-Related Biomarkers in Heart Failure with Reduced Ejection Fraction: Association of Serum HMGN2 with Prevalent Heart Failure and Its Diagnostic Performance

Background/Objectives: Lactate and lactylation are associated with the development of heart failure with reduced ejection fraction (HFrEF). This study aimed to identify potential lactylation-related biomarkers with diagnostic and prognostic value in patients with HFrEF. Methods: We identified the potential lactylation-related biomarkers for heart failure (HF) by integrating bioinformatics analysis with machine learning algorithms. A total of 251 patients with HFrEF and 210 adults without HF were enrolled to validate the diagnostic values of lactylation-related biomarkers at both the mRNA and protein levels. Results: Bioinformatics analysis and machine learning identified EIF4G1, HLTF, HMGN2, LSP1, and PPM1G as hub lactylation-related genes in patients with HF. In the external validation cohort, elevated serum high-mobility group nucleosomal-binding domain 2 (HMGN2) levels were significantly associated with HFrEF. Beyond its diagnostic utility in HFrEF, HMGN2 was associated with prevalent HFrEF (AUC 0.81, 95% CI 0.77–0.85). In exploratory 12-month follow-up, higher HMGN2 was associated with poor outcomes. Conclusions: HMGN2 is a lactylation-associated biomarker that is elevated in patients with HFrEF, associated with prevalent HFrEF, and shows promise for risk stratification with diagnostic discrimination.