Exploring a critical time window for FOXM1-driven bladder injury in chronic arsenic exposure

Chronic inorganic arsenic (iAs) exposure is a global public health concern and a well‑established risk factor for bladder cancer; however, the molecular mechanisms by which iAs exposure drives the transition from reversible injury to irreversible transformation remain poorly understood. Here, we investigated the role of the transcription factor forkhead box M1 (FOXM1) in this process by integrating public transcriptomic and clinical cohort analyses, protein-protein interaction and pathway enrichment analyses, chronic arsenic-exposed mouse models, arsenic speciation analysis, histopathological assessment, RNA sequencing, molecular validation, and functional assays in human urothelial cells. Bioinformatics analysis identified FOXM1 as a key node linking iAs-responsive genes to cell-cycle pathways, with its expression correlating with poor prognosis and tumor stemness in human bladder cancer cohorts. In a mouse model exposed to arsenic for 56, 120, and 365 days, we observed progressive bladder tissue injury accompanied by sustained FOXM1 upregulation. Transcriptomic profiling further established FOXM1 as a central network hub in arsenic-induced gene dysregulation. Using a chronic iAs-induced cellular reprogramming model in human urothelial cells, we demonstrated that chronic arsenic exposure drives FOXM1-dependent entry into an irreversible proliferative state after 3-4 months, which persists despite FOXM1 inhibition. Furthermore, FOXM1 overexpression synergized with iAs to enhance proliferative responses through downstream cell-cycle effectors CCNB1 and CDC25B. Collectively, these findings suggest that chronic iAs exposure promotes FOXM1-associated bladder epithelial alterations through cell cycle dysregulation, with FOXM1 representing a potential early intervention target in iAs-related bladder pathology.