Toxicological Impacts of Arecoline and Tobacco in Oral Submucous Fibrosis: Mechanisms and Therapeutic Insights

ABSTRACT Oral submucous fibrosis (OSMF) is an oral potentially malignant disorder associated with a high risk of malignant transformation, characterized by the excessive accumulation of extracellular matrix (ECM). The primary etiological factors contributing to OSMF include betel nut chewing, smoking, and tobacco use, with or without alcohol consumption. Exposure to betel nut, smokeless tobacco extracts, and cigarette smoke induces cytotoxicity in oral epithelial cells through apoptosis and oxidative stress, while simultaneously promoting fibroblast proliferation and ECM synthesis. Arecoline, a major alkaloid in betel nut, contributes to epithelial atrophy, senescence, and apoptosis. It also activates the JNK/ATF2/Jun pathway, leading to the activation of transforming growth factor (TGF)‐β signaling in epithelial cells. TGF‐β1 signaling, initiated by epithelial cells, activates fibroblasts in a paracrine manner, facilitating their transition to myofibroblasts and resulting in excessive ECM deposition within the OSMF microenvironment. Furthermore, arecoline stimulates fibroblast proliferation and activates the TGF‐β1/SMAD signaling pathway, thereby promoting ECM synthesis. From a therapeutic perspective, intralesional administration of corticosteroids (such as dexamethasone, betamethasone, hydrocortisone, or triamcinolone) combined with hyaluronidase and antioxidants has shown improvements in mouth opening, burning sensations, and overall quality of life in OSMF patients. Additionally, herbal medicines such as curcumin and aloe vera have demonstrated efficacy, particularly in enhancing tongue protrusion and alleviating burning sensations, respectively. Lycopene and salvianolic acid B have also proven beneficial in relieving clinical symptoms and contributing to the long‐term management of OSMF.