Serum Copper and Heart Failure: A Cross-Sectional and In Silico Toxicological Study

Heart failure (HF) is a major public health concern marked by substantial morbidity and mortality. Emerging evidences suggest that copper (Cu) may be implicated in cardiovascular diseases, but its relationship with HF remains inadequately understood. This study was conducted to investigate the association between serum copper levels and the prevalence of HF, while exploring potential underlying mechanisms using network toxicology. Data were derived from 5139 participants aged 18-80 years in the NHANES 2011-2016 cycle. Serum copper levels were measured using inductively coupled plasma dynamic reaction cell mass spectrometry (ICP-DRC-MS). Logistic regression and restricted cubic spline models were employed to evaluate the association between serum copper and HF. A network toxicology approach, incorporating database mining (CTD and ChEMBL), protein-protein interaction (PPI) network analysis, Gene Ontology (GO), and KEGG pathway enrichment, was utilized to elucidate potential molecular mechanisms. Elevated serum copper levels were significantly associated with increased prevalence of HF (OR 1.08, 95% CI 1.03-1.13; p = 0.0008). A significant sex-based interaction was observed, with a stronger association evident among males. Through in silico analysis, a total of 108 copper-related HF target genes were identified, with TP53, IL-1B, IL-6, TNF, AKT1, and ALB recognized as hub genes. Enriched KEGG pathways included lipid metabolism and atherosclerosis, apoptosis, MAPK signaling, ROS-mediated chemical carcinogenesis, and AGE-RAGE signaling in diabetic complications. Mechanistically, copper-induced oxidative stress, apoptosis, and immune dysregulation were implicated in HF pathogenesis. Serum copper levels demonstrate an independent association with HF prevalence. However, due to the cross-sectional design of the study, causal inference cannot be established. Network toxicological analysis highlights key biological pathways such as oxidative stress and apoptosis, offering mechanistic insights into the role of copper in HF development.