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

Abstract

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.

Key Findings

• Nrf2 signaling is a master regulator of cellular antioxidant defense mechanisms.
• Vitamin D3 (VitD3), beyond its classical roles, exhibits anti-inflammatory and antioxidant properties.
• Calcitriol, the active form of VitD3, can modulate the Nrf2 pathway and enhance downstream protective responses.

Clinical Significance

Citation

Tajgardan Asal, Azami Tameh Abolfazl, Barati Shirinet al.. The interplay between vitamin D3 and Nrf2 signaling: mechanistic insights and therapeutic potentials. Naunyn-Schmiedeberg's archives of pharmacology. 2026-Oct-03.