Targeting oral cancer with curcumin and its structural analogs: molecular mechanisms, pharmacokinetic optimization, and clinical translation.

Curcumin is a naturally occurring polyphenol extracted from turmeric (Curcuma longa) and is known for its diverse biological functions, such as antioxidant, anti-inflammatory, anti-migratory, and anticancer activities. However, its use in clinical cancer treatment remains constrained due to challenges like limited absorption, rapid metabolic breakdown, a short half-life, and generally low bioavailability. To overcome these limitations, various curcumin analogs and formulation strategies have been developed to enhance its therapeutic efficacy. In oral cancer, a malignancy characterized by high recurrence rates, therapeutic resistance, and substantial treatment-related morbidity, novel multi-targeted and low-toxicity strategies remain urgently needed. Yet, the intersection between curcumin's pharmacological constraints and the specific therapeutic vulnerabilities of oral cancer has not been critically synthesized. This review addresses this gap by integrating pharmacokinetic limitations, molecular mechanisms of action, and disease-specific signaling dependencies in oral cancer. We systematically examine evidence demonstrating that curcumin and its derivatives suppress proliferation, invasion, metastasis, angiogenesis, and inflammatory signaling through modulation of pathways such as nuclear factor-κB (NF-κB), phosphoinositide 3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK), and apoptosis-related cascades. Importantly, we critically evaluate next-generation curcumin analogs and advanced delivery systems that are designed to overcome bioavailability barriers and enhance tumor-specific efficacy. Collectively, the available evidence positions curcumin as an investigational multi-target scaffold, with its clinical translation in oral cancer dependent on rational formulation strategies and rigorous validation. Bridging mechanistic insights with pharmacokinetic optimization and well-designed clinical trials will be essential to define the therapeutic value of optimized curcumin-based adjunctive approaches.