Molecular mechanisms of therapeutic resistance in areca nut-associated oral squamous cell carcinoma: the interplay of chronic inflammation and epithelial-mesenchymal transition.

Oral squamous cell carcinoma (OSCC) is a significant form of oral cancer prevalent in South and Southeast Asia, where areca nut chewing is widespread. Chronic exposure to areca nut alkaloids, such as arecoline, contributes to oral carcinogenesis by inducing oxidative stress, DNA damage, chronic inflammation, fibrosis, and epithelial-mesenchymal transition (EMT). These pathological changes facilitate the development of potentially malignant lesions, including oral submucous fibrosis, and promote tumour progression, metastasis, immune evasion, and treatment resistance. Several molecular pathways, including NF-κB, MAPK/ERK, TGF-β, Wnt/β-catenin, and Notch signalling, are integral to areca nut-associated carcinogenesis. Persistent inflammatory signalling and EMT contribute to a tumour promoting microenvironment, characterised by extracellular matrix remodelling, stromal activation, and cancer stemness. Changes associated with EMT, such as the loss of E-cadherin and increased expression of N-cadherin and vimentin, enhance cellular migration and invasion and resistance to treatment. Chronic inflammation and EMT contribute to chemoresistance and radiotherapy resistance through mechanisms such as autophagy induction, hypoxia, anti-apoptotic signalling, and the maintenance of cancer stemness. Recent evidence indicates that targeting inflammatory mediators, reactive oxygen species (ROS), and EMT related pathways may enhance therapeutic outcomes in OSCC associated with areca nut consumption. This review summarises the molecular mechanisms linking areca nut exposure to OSCC progression, focusing on the interaction between chronic inflammation and EMT, and examines their implications for tumour aggressiveness, therapeutic resistance, and future targeted therapeutic strategies.