Cadmium exposure triggers a functional switch of APP to drive joint degeneration

Cadmium (Cd) is a pervasive environmental heavy metal linked to various chronic pathologies; however, its specific role and underlying molecular mechanisms in osteoarthritis (OA) pathogenesis remain poorly characterized. We performed a cross-sectional analysis using the NHANES database (2001–2018) to evaluate the association between blood Cd levels and OA risk. Hub targets were identified by integrating the CTD and GEO databases through network toxicology and machine learning algorithms. Single-cell RNA sequencing (scRNA-seq) was employed to resolve the cellular localization and dynamic shifts of these targets. Causal relationships were substantiated via drug-target Mendelian randomization (MR) analysis. Findings were further corroborated through molecular docking, 100-ns molecular dynamics (MD) simulations, and an independent retrospective clinical cohort consisting of 180 OA patients and 400 cervical spondylosis controls, in which peripheral blood inflammatory markers were evaluated for clinical validation. Cross-sectional analysis revealed a significant positive association between blood Cd concentrations and OA prevalence, with a robust dose-response relationship (OR per log-unit = 1.64, P < 0.001). Multi-omics integration identified APP (Amyloid Precursor Protein) as a pivotal Cd-associated hub gene. scRNA-seq localized APP overexpression predominantly within fibrocartilage cells (FC), with notable upregulation across OA-derived chondrocyte subpopulations. While MR analysis suggested an inherent protective causal effect of APP against OA risk, this physiological role appears disrupted by the Cd-induced inflammatory milieu, where aberrant APP processing likely promotes cartilage matrix degradation. Retrospective clinical validation further demonstrated systemic immune dysregulation in OA patients, with inflammatory markers including WBC, monocytes, SII, and NLR showing robust diagnostic performance (AUC > 0.9), thereby providing clinical evidence supporting the involvement of the APP-associated immune-inflammatory axis. Furthermore, MD simulations suggested a possible binding mode between NAC and APP with modest affinity, providing preliminary structural insights that warrant further experimental validation. This study systematically elucidates the molecular landscape through which Cd exposure drives OA progression via the APP-mediated immune-inflammatory axis. These findings provide a novel theoretical framework for early screening and targeted therapeutic strategies in populations at high risk of environmental heavy metal exposure. Integrated epidemiological, multi-omics, and molecular analyses reveal that cadmium (Cd) exposure promotes osteoarthritis (OA) progression through an APP-mediated immune-inflammatory axis. Cd-associated molecular alterations identify APP as a key hub gene localized in OA-related chondrocyte populations and linked to monocyte/macrophage activation and joint microenvironment remodeling. Genetic evidence, computational structural analysis, and clinical validation further support the involvement of APP and systemic inflammatory signatures in OA. This study provides insights into environmental heavy metal-induced joint degeneration and potential strategies for early risk assessment and targeted intervention.