Molecular mechanism of lead exposure induced atrial fibrillation: A systematic study based on network toxicology, machine learning, and in vivo and in vitro experiments

Lead is a ubiquitous environmental toxic metal. Lead exposure is closely linked to an increased risk of atrial fibrillation (AF), yet its molecular mechanism remains incompletely understood. Here, we conducted an integrated study using network toxicology, machine learning, molecular docking, and in vivo and in vitro experiments to explore lead-induced AF. The global burden of disease analysis showed a marked rise in lead exposure-related AF/atrial flutter mortality and disability‑adjusted life years from 1990 to 2021, especially in low socio‑demographic index regions. We identified 142 overlapping targets between lead exposure and AF. Protein-protein interaction network and machine learning identified MAPK3 and ALB as core hub genes. Functional enrichment indicated critical roles of the PI3K‑Akt pathway. Molecular docking verified strong binding between Pb²⁺ and key pathway proteins. Lead exposure in mice triggered atrial electrical and structural remodeling and increased AF inducibility. In vitro, lead inhibited PI3K‑Akt phosphorylation, which was prevented by the pathway agonist 740 Y‑P. In conclusion, lead exposure was shown to promote AF by suppressing the PI3K‑Akt pathway, with MAPK3 and ALB as key targets. This study provides mechanistic insight and potential intervention targets for lead exposure-related AF.