Translational Evaluation of Beetroot-Derived Betanin in Oral Cancer Using a Sequential AI-Guided Evidence Framework

Abstract

Oral cancer, particularly oral squamous cell carcinoma (OSCC), remains a major global health challenge due to its high morbidity, late-stage diagnosis, and limited therapeutic efficacy. The disease is characterized by complex and interconnected molecular mechanisms, including dysregulation of PI3K/AKT/mTOR, MAPK/ERK, NF-κB, and STAT3 signaling pathways, along with oxidative stress imbalance, immune evasion, and resistance to apoptosis. These multifactorial processes necessitate the development of multi-target therapeutic strategies. Beetroot (Beta vulgaris), a nutritionally rich medicinal plant, contains diverse bioactive compounds such as betalains (notably betanin), flavonoids, and phenolic acids, which exhibit antioxidant, anti-inflammatory, and anticancer properties. Despite increasing evidence supporting its anticancer potential, systematic evaluation of beetroot-derived compounds in oral cancer remains limited. In this study, a structured AI-guided translational framework was employed to investigate the therapeutic potential of beetroot-derived phytoconstituents in oral cancer. The framework was organized into six sequential modules, including target identification, lead optimization, in vitro validation design, in vivo translational modeling, clinical strategy development, and market regulatory alignment. Mechanistic insights revealed that beetroot bioactives modulate key oncogenic pathways by inhibiting NF-κB and STAT3 signaling, inducing apoptosis via caspase activation, regulating oxidative stress through Nrf2 pathways, and suppressing angiogenesis by downregulating VEGF expression. Network-based intersection analysis demonstrated a significant overlap between oral cancer-associated genes and beetroot targets, supporting the biological plausibility of these interactions. Overall, this study establishes a comprehensive and scalable framework for evaluating beetroot-derived compounds as multi-target therapeutic candidates in oral cancer. Although current evidence remains largely preclinical, the findings highlight strong mechanistic relevance and translational potential, warranting further experimental and clinical validation.