Molecular Mechanisms of DBNL in Heart Failure: From Macrophage Immunometabolism to Therapeutic Implications

Heart failure (HF) remains a major global health challenge, with limited effective treatments targeting its core pathophysiological mechanisms. In this study, an integrated multiomics approach combining Mendelian randomization (MR) and single-cell RNA sequencing (scRNA-seq) was used to identify potential biomarkers and therapeutic targets for HF. We utilized data from genome-wide association studies (GWASs), expression quantitative trait loci (eQTLs), methylation quantitative trait loci (mQTLs), and protein quantitative trait loci (pQTLs) to investigate the genetic mechanisms of HF. Single-cell RNA sequencing was performed to analyse gene expression in cardiac macrophages, and pseudotime analysis was used to study the dynamic regulation of DBNL during macrophage differentiation. Molecular docking and dynamics simulations identified pirinixic acid (WY-14643; PubChem CID: 4594; synonyms: 50892-23-4; WY-14643) as a potential regulator of DBNL. Multiomics analysis revealed that DBNL (Drebrin-like) is a key gene associated with HF risk. Single-cell RNA sequencing revealed that DBNL is expressed mainly in cardiac macrophages and is upregulated under pathological conditions. The expression of DBNL by macrophages is associated with immune metabolism and profibrotic pathways, particularly the IL-6/JAK/STAT3, PI3K/AKT/mTOR, and TGF-β signalling pathways. Pseudotime analysis indicated that DBNL has a dynamic regulatory effect on macrophage differentiation, especially in chronic inflammation. Molecular docking and dynamic simulations have shown that pyridine acid has a potential role in regulating DBNL. This study elucidates the role of DBNL in the progression of heart failure and suggests its potential as a therapeutic target. Importantly, the therapeutic relevance is inferred from computational predictions. These findings offer novel insights into immune metabolism and macrophage-mediated intercellular communication, establishing a theoretical basis for future applications in the optimization of DBNL-targeted drugs and functional research. Nonetheless, additional experimental validation and preclinical studies are needed to substantiate the clinical efficacy of DBNL as a therapeutic target.