5-Fluorouracil exacerbates oral mucositis through inflammation and fibroblast-mediated matrix imbalance

Abstract

Abstract Oral mucositis (OM) is a critical complication of cancer chemotherapy that can lead to treatment interruption or discontinuation and adversely affect patient prognosis. Here, we established a 5-fluorouracil (5FU)-exacerbated OM model to elucidate the mechanism underlying chemotherapy-associated OM aggravation and evaluate the effects of a mouthwash (MW) containing antimicrobial (cetylpyridinium chloride) and anti-inflammatory components (glycyrrhizin, tranexamic acid, and Equisetum arvense extract). In this model, 5FU markedly enhanced subepithelial inflammation at the wound site, whereas MW treatment reduced inflammation and promoted mucosal healing. RNA sequencing and in vitro fibroblast analyses demonstrated that 5FU significantly upregulated Gremlin 1 ( Grem1 ), matrix metallopeptidase 3 ( Mmp3 ), and plasminogen activator, urokinase ( Plau ), while suppressing fibroblast growth factor 10 ( Fgf10 ). Scratch assays further revealed that 5FU impaired fibroblast migration and proliferation, which were restored by anti-inflammatory MW components, accompanied by normalization of Grem1 and Fgf10 expression. Collectively, these findings provide mechanistic insight into 5FU-exacerbated OM and suggest that modulation of fibroblast-associated inflammatory and regenerative pathways by MW may represent a promising strategy for OM management during chemotherapy.