HMOX2 and HSPA2 Are Lysine β-Hydroxybutyrylation–Related Biomarkers in Heart Failure

Background Lysine β-hydroxybutyrylation (Kbhb) had a complex role in heart failure (HF), yet its mechanisms remained unclear. This study aimed to identify Kbhb-related biomarkers in HF and to elucidate their mechanisms, thereby providing a theoretical basis for diagnosis and targeted therapy. Methods Transcriptome data and lysine β-hydroxybutyrylation–related genes (Kbhb-related genes, KRGs) were obtained from public databases and published literature. Differential expression analysis and intersection filtering were performed to identify Kbhb-related candidate genes in heart failure (HF), and multiple machine-learning algorithms were applied to select biomarkers. Biomarkers were then confirmed in training and validation cohorts by expression verification and receiver operating characteristic (ROC) analyses, followed by construction and validation of a nomogram.Subsequently,GeneMANIA analysis, chromosomal localization, molecular regulatory network construction, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA), and immune-infiltration analysis were conducted to explore mechanisms related to the biomarkers. Finally, potential therapeutic targets for HF were investigated through drug prediction and molecular docking. Results A total of 448 differentially expressed genes (DEGs) were intersected with 1,493 Kbhb-related genes (KRGs) to yield 12 candidate genes, from which HMOX2 and HSPA2 were ultimately identified as biomarkers. The nomogram demonstrated favorable predictive performance. Through regulation by specific microRNAs and long non-coding RNAs, HMOX2 and HSPA2 formed a molecular regulatory network comprising 59 nodes and 107 edges. Gene set enrichment analysis (GSEA) suggested that HF progression was associated with pathways such as interferon-γ response, MYC targets, epithelial–mesenchymal transition, Fcγ receptor–mediated phagocytosis, TNF-α/NF-κB signaling, and oxidative phosphorylation. In addition, 20 immune-cell subsets exhibited significant differences in infiltration, including activated B cells. The drug–biomarker interaction network (90 nodes with 103 interactions) indicated that HMOX2 and HSPA2 showed high binding affinity with valproic acid. Conclusions Through transcriptomic analyses, this study identified HMOX2 and HSPA2 as biomarkers, which provided new avenues for investigating Kbhb-related mechanisms in heart failure.