Microcystin-LR exposure induces cartilage degeneration and dysregulates osteoarthritis-associated targets: an integrative computational and experimental study

Introduction Microcystin‐LR (MC‐LR), a prevalent cyanotoxin in eutrophic freshwater, is becoming a more widespread environmental contaminant as global warming promotes cyanobacterial blooms, and its health effects may extend beyond its well-documented hepatotoxicity. Methods Here, we integrated network toxicology, machine learning, molecular dynamics simulation (MDS), and in vitro and in vivo experiments to investigate the role of MC‐LR in osteoarthritis (OA). A total of 368 predicted MC‐LR targets were intersected with OA‐related differentially expressed genes from five batch-corrected Gene Expression Omnibus (GEO) datasets. Results Weighted gene co-expression network analysis (WGCNA) identified a disease-correlated red module (r = 0.61, p = 2.3e–13), and least absolute shrinkage and selection operator (LASSO) regression narrowed the candidates to a six‐gene diagnostic signature (FAP, IGF1R, IGF1, MMP9, CRABP2, and ITGA4), with a combined area under the curve (AUC) of 0.910. CIBERSORT analysis indicated altered macrophage polarization and T‐cell redistribution within the osteoarthritic microenvironment. Molecular docking and 100-ns MDS showed that MC‐LR formed thermodynamically favorable and stable complexes with the five upregulated core targets, with FAP exhibiting the strongest binding affinity (–10.3 kcal/mol). In human chondrocytes, MC-LR exposure was cytotoxic (IC 50 = 13.09 μM) and upregulated the mRNA levels of CRABP2, FAP, IGF1, ITGA4, and MMP9, consistent with the in silico predictions. Intra-articular injection of MC‐LR in mice induced dose-dependent knee cartilage degeneration, with matrix loss and elevated OARSI scores. Discussion Together, these findings associate MC‐LR exposure with cartilage degeneration under experimental conditions and implicate PI3K‐Akt signaling, focal adhesion, and extracellular matrix remodeling as candidate mechanisms, extending the recognized effects of cyanotoxins beyond the liver and highlighting chronic pollutant exposure as an underrecognized potential risk factor for degenerative joint disease.