Nrf2 signaling pathway exhibits dual role in oral squamous cell carcinoma, promoting progression and resistance

Oral squamous cell carcinoma (OSCC) progression is significantly influenced by oxidative stress, which disrupts cellular redox homeostasis and gene regulation. Current therapeutic approaches often face challenges due to treatment resistance. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is a crucial regulator of antioxidant defense, activating cytoprotective genes under stress. However, its complex role in cancer, particularly OSCC, suggests a potential

Researchers conducted a comprehensive literature review to evaluate the intricate roles of oxidative stress and the Kelch-like ECH-associated protein-1 (Keap1)/Nrf2 signaling pathway in oral squamous cell carcinoma (OSCC). The methodology involved synthesizing existing scientific literature to highlight how these factors contribute to the development, progression, and therapeutic resistance of OSCC. The study aimed to consolidate findings on Nrf2's dual function, examining its protective mechanisms in normal cells versus its oncogenic activities in cancer cells, without involving experimental protocols or specific compound testing.

The review revealed that while Nrf2 effectively protects normal cells from oxidative damage, its persistent activation within cancer cells paradoxically promotes tumor progression. This sustained Nrf2 activity drives metabolic reprogramming, enhancing cancer cell survival and contributing to resistance against both chemotherapy and radiotherapy. Dysregulation of the Keap1/Nrf2 axis was specifically identified as a key factor that enhances cancer cell survival and contributes to radioresistance in OSCC. This highlights a critical dichotomy: > Nrf2 displays a dual function, acting as both a tumor suppressor in healthy tissues and a tumor promoter in established cancers, particularly in the context of therapeutic resistance. The pathway's ability to activate cytoprotective genes, while beneficial in normal cells, becomes a liability in cancer, fostering an environment conducive to uncontrolled growth and evasion of treatment-induced damage.