The interplay between vitamin D3 and Nrf2 signaling: mechanistic insights and therapeutic potentials.

Oxidative stress plays a central role in the initiation and progression of numerous pathological conditions, including neurodegenerative, cardiovascular, metabolic, hepatic, and inflammatory disorders. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is recognized as a master regulator of cellular antioxidant defense, mediating the transcription of a wide array of antioxidant and cytoprotective genes. Beyond its classical role in calcium and bone homeostasis, vitamin D3 (VitD3) exerts a broad spectrum of non-classical biological effects. Accumulating evidence highlights its anti-inflammatory, anti-oxidative, anti-angiogenic, and anti-cancer properties, while VitD3 deficiency has been implicated in the pathogenesis of various cardiovascular, inflammatory, and malignant diseases. Among these emerging non-calcemic functions, the antioxidant capacity of VitD3 has gained increasing attention. Recent studies suggest that calcitriol, the active form of VitD3, may modulate the Nrf2 signaling pathway and its downstream protective responses. This review synthesizes current evidence on the potential role of VitD3-mediated Nrf2 modulation across diverse disease models. Collectively, targeting the VitD3-Nrf2 axis may represent a promising mechanistic target for future therapeutic investigation.