Long Non-coding RNAs in Radiation-induced Oral Mucositis: Bridging Cancer Biology and Mucosal Injury

Objective: Radiation-induced oral mucositis (RIOM) is one of the most painful and treatment-limiting toxicities of head and neck cancer (HNC) therapy, often leading to unplanned treatment breaks, dose reductions, compromised oncologic outcomes, and death. Despite its clinical significance, RIOM remains largely unexplored in terms of molecular predictors and prognostic markers. This review bridges radiation biology, transcriptomics, and clinical oncology to reveal how long non-coding RNAs (lncRNAs) orchestrate the injury-repair cycle of irradiated oral mucosa. Methods: This review was conducted by a structured screening process to ensure comprehensive coverage of relevant literature. Publications on lncRNAs associated with RIOM were retrieved from PubMed, Web of Science, and clinical trials databases using keywords such as “lncRNAs in RIOM,” “lncRNAs in radiation-induced oral mucositis,” “lncRNAs in oral mucosa,” “lncRNAs in radiation-induced DNA damage and oxidative stress,” “lncRNAs in radiation-induced inflammation,” and “lncRNAs in radiation therapy in head and neck cancer.” Priority was given to studies directly examining lncRNA expression in normal oral mucosa under radiation stress, with additional contextual evidence drawn from cancer and other epithelial injury models when RIOM-specific data were lacking. Results: Direct transcriptomic studies of lncRNAs in radiation-exposed normal oral mucosa are scarce. Limited evidence suggests that certain lncRNAs, such as MALAT1 and NEAT1, respond to radiation and influence inflammation, DNA damage repair, and epithelial regeneration. In cancer and other tissue injury contexts, additional lncRNAs, including MEG3, TUG1, and TP53COR1, have been implicated in the regulation of oxidative stress and apoptosis, processes relevant to RIOM pathophysiology. While these findings have not yet been validated in normal irradiated oral mucosa, they highlight biologically plausible candidates for future investigation. Addressing this gap will require integrated approaches that combine pretreatment lncRNA profiling, functional validation in relevant in vitro and in vivo models, and longitudinal patient studies to link molecular signatures with clinical outcomes. Conclusion: Current knowledge of lncRNAs in RIOM is largely extrapolated from cancer biology and other epithelial injury models. By prioritizing oral tissue-specific profiling and functional validation under radiation conditions, future research could identify novel biomarkers and therapeutic targets, ultimately enabling precision-guided prevention and management of RIOM. Moreover, proteins regulated by these lncRNAs (if detectable in saliva or serum) could be adapted into rapid, point-of-care lateral flow assays (LFAs) for early clinical decision-making, transforming a currently reactive management paradigm into a proactive, personalized approach.