Therapeutic Potential of Melatonin in Gastrointestinal Cancers: Molecular Mechanisms, Preclinical Evidence and Clinical Implications

Gastrointestinal (GI) cancers remain a leading cause of global morbidity and mortality, necessitating novel therapeutic strategies. Melatonin (MEL), an indoleamine with pleiotropic biological activities, has emerged as a promising adjuvant in oncology due to its antiproliferative, proapoptotic, and antioxidant properties. This review synthesizes current evidence on MEL's molecular mechanisms in GI carcinogenesis, including modulation of NF‐κB, PI3K/AKT, and Wnt/β‐catenin pathways, suppression of reactive oxygen species (ROS), and regulation of circadian rhythm‐related genes (e.g., CLOCK, BMAL1). Preclinical studies demonstrate that MEL enhances chemoradiotherapy efficacy‐reducing tumor volume by 70% in murine colorectal models and decreasing 5‐fluorouracil (5‐FU) resistance via miR‐532‐3p/β‐catenin axis modulation. Clinical trials report a 23%–41% risk reduction in colorectal cancer among shift workers with MEL supplementation and a 53% decrease in radiotherapy‐induced oral mucositis. Despite promising data, limitations persist: fewer than 15% of clinical trials focus on GI cancers, dosing remains unstandardized (10–40 mg/day), and molecular heterogeneity (e.g., KRAS mutations in pancreatic cancer) may limit therapeutic responses. Future research must prioritize phase III trials, chronotherapy optimization, and biomarker‐driven approaches, including MT1/MT2 receptor expression and microbiome profiling. Given its low toxicity and putative synergy with immunotherapies, MEL should be regarded as an adjunct under investigation rather than an established option; to date, no GI‐specific phase III randomized trials exist, and clinical signals come primarily from small, heterogeneous cohorts. Dosing is unstandardized and limited by low oral bioavailability (first‐pass) and possible pharmacogenomic variability.