Abstract
The areca nut (AN) is chewed by approximately 600 million people worldwide. Among AN chewers, ~5% develop oral submucosal fibrosis (OSF), a progressive fibrotic disorder of the oral cavity. OSF is characterized by subepithelial fibrosis and mucosal rigidity, leading to restricted mouth opening, difficulty in mastication, deglutition, and speech. These impairments severely compromise oral hygiene and routine dental care, diminishing patients' quality of life. At least 4% of OSF patients develop oral cancer. The prevalence of OSF correlates with AN chewing, particularly when accompanied by other risk factors such as tobacco use. The International Agency for Research on Cancer has identified chronic chemical and mechanical irritation of the oral mucosa from AN chewing as a major cause of OSF. The active chemical ingredients of AN include alkaloids such as arecoline, flavonoids, and tannins. Of these, arecoline is considered the most potent fibrogenic agent. In vitro, arecoline induces cultured fibroblasts to differentiate into highly contractile α-smooth muscle actin (α-SMA)-expressing myofibroblasts, the effector cells of fibrosis, and to express profibrotic markers and mediators, including transforming growth factor-β 1 (TGF-β1) and cellular communication network factor 2 (CCN2), which is associated with malignant progression of OSF. In vivo, mice exposed to AN extract or arecoline show submucosal collagen accumulation and myofibroblast differentiation, concomitant with upregulated pro-fibrotic gene (TGF-β1, Col1A1, α-SMA) expression. Although myofibroblasts can be seen in OSF patient-derived samples, substantial disease heterogeneity exists, which has thus far hindered the generation of high-quality data necessary to gain insights into underlying mechanisms and disease progression. Consequently, treatment options for OSF are limited and primarily symptomatic. Collectively, evidence from human and animal studies establishes OSF as an AN-induced fibrotic disorder and underscores the urgent need for mechanism-focused research to identify reliable diagnostic markers and therapeutic targets to address its growing global burden.