Betel quid may stimulate oral submucous fibrosis by inducing increased mitochondrial reactive oxygen species generation via copper overload

Abstract

Betel quid (BQ), a smokeless chewing tobacco that includes the areca (betel) nut among its ingredients, increases the risk of oral submucous fibrosis (OSMF) and oral cancer, a disease classified as an potentially malignant oral disorder. A wound from the coarse areca nut fibers, as well as the catechin, copper, and alkaloids (e.g., arecoline, arecaidine, guvacoline, and guvacine) in BQ, may stimulate reactive oxygen species (ROS) production, causing myofibroblast differentiation and contraction, fibroblast proliferation, collagen cross-linking, and collagen phagocytosis inhibition, which could result in OSMF and oral cancer. Mitochondria, the primary source of ROS in OSMF, play a crucial role in cellular metabolism. Copper is required for mitochondrial bioenergetics, dynamics, and mitophagy, affecting metabolic reprogramming and cell fate. Given that copper levels are elevated in patients with OSMF, we hypothesize that increased mitochondrial ROS production induced by copper overload and areca nut components may regulate fibrosis-related gene expression and myofibroblast differentiation. Therefore, targeting this fundamental pathomechanism is an appropriate strategy for developing new therapeutic options for OSMF.