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Chronic areca nut alkaloid exposure drives oxidative stress and DNA damage, sustaining chronic inflammation and promoting fibrosis and epithelial–mesenchymal transition (EMT). These changes remodel the extracellular matrix, activate stroma, enhance cancer stemness, and accelerate tumor progression, metastasis, immune evasion, and therapy resistance. Key signaling routes (NF-κB, MAPK/ERK, TGF-β, Wnt/β-catenin, Notch) link inflammation and EMT to chemo- and radiotherapy resistance, suggesting that targeting inflammatory mediators, ROS, and EMT-related pathways may improve 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\nUniversity Hospital RWTH Aachen, Germany  \nREVIEWED BY  \nViji Remadevi,  \nUniversity of Kansas Medical Center, United States  \nShuai Yang,  \nXuzhou Medical University, China  \n*CORRESPONDENCE  \nMehta Vedant Kamal  \n[vedant29599@gmail.com](vedant29599@gmail.com)  \nRECEIVED 11 June 2026  \nREVISED 24 July 2026  \nACCEPTED 28 July 2026  \nPUBLISHED 10 August 2026  \nCITATION  \nJoshi K, P. R., Raju D, H. D. S, Shenoy Belle V, Kumar NAN and Kamal MV (2026) Molecular mechanisms of therapeutic resistance in areca nut– associated oral squamous cell carcinoma: the interplay of chronic inflammation and epithelial– mesenchymal transition.  \nFront. Oncol. 16:1906691 .  \ndoi: 10.3389/fonc.2026.1906691  \nCOPYRIGHT  \n© 2026 Joshi, P. R., Raju, H. D., Shenoy Belle, Kumar and Kamal. This is an openaccess article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.  \nMolecular mechanisms of therapeutic resistance in areca nut–associated oralsquamous cell carcinoma:  \nthe interplay of chronic inflammation and epithelial– mesenchymal transition  \nKaushik Joshi 1, Arya P. R. 1, Dipali Raju 2, Shilpa H. D. 1, Vijetha Shenoy Belle 3, Naveena A. N. Kumar 2 and Mehta Vedant Kamal 1*  \n1 Department of Biochemistry, Dr. Chandramma Dayananda Sagar Institute of Medical Education and Research, Dayananda Sagar University, Deverakaggalahalli, Karnataka, India, 2 Department of Surgical Oncology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India, 3 Department of Biochemistry, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India  \nOral 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-kB, MAPK/ERK, TGF-b, Wnt/ b-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.  \nKEYWORDS  \nareca nut, chronic inflammation, epithelial-mesenchymal transition, oral squamous cell carcinoma, treatment resistance  \nFrontie","cbCaiswcPlYz11y5","https://ap.wps.com/l/cbCaiswcPlYz11y5","pdf",3133405,15,"English","# Introduction\n## Areca nut chewing as a risk factor for OSCC\n## Molecular links between areca nut exposure, inflammation, DNA damage, EMT, and resistance\n# Molecular mechanisms of therapeutic resistance\n## Chronic inflammation-driven signaling and tumor microenvironment\n## EMT-associated phenotypic changes and treatment resistance\n# Therapeutic implications and future directions","[{\"question\":\"How might targeting inflammation, ROS, or EMT improve therapy outcomes?\",\"answer\":\"The document notes evidence that targeting inflammatory mediators, reactive oxygen species, and EMT-related pathways may enhance therapeutic outcomes in OSCC linked to areca nut consumption by disrupting mechanisms that sustain aggressiveness and treatment resistance.\"}]","Molecular mechanisms of therapeutic resistance in areca nut–associated oral squamous cell carcinoma: the interplay of chronic inflammation and epithelial–mesenchymal transition - Review | PDF",1790155227,38]