This review proposes that combined vitamin D3 and vitamin A therapy could synergistically activate the VDR-RXR heterodimer to upregulate neuroprotective genes and reduce inflammation/oxidative stress, and calls for molecular-to-clinical validation.

Offers a repurposing-friendly, mechanistically plausible hypothesis linking VDR-RXR signaling to neuronal resilience that could direct preclinical PD studies and biomarker development, but is limited by being a speculative review with little PD-specific in vivo or clinical evidence.

Neurodegenerative diseases such as Alzheimer's and Parkinson's disease are characterized by progressive neuronal loss, oxidative stress, and limited treatment options. While vitamin D₃ has demonstrated neuroprotective potential, we hypothesize that its co-administration with vitamin A may enhance therapeutic effects via synergistic interactions between their nuclear receptors (the vitamin D Receptor (VDR) and Retinoid X Receptor (RXR)). The interaction leads to the formation of a heterodimer, which regulates genes involved in neuronal survival, inflammation, and oxidative balance. A comprehensive literature review was conducted to evaluate the mechanisms underlying Vitamin D₃'s neuroprotection and Vitamin A's modulatory role through RXR activation, focusing on studies exploring the VDR-RXR heterodimer in Alzheimer's and Parkinson's disease models. Evidence indicates that vitamin D₃ mitigates neurodegeneration by upregulating neuroprotective genes, reducing oxidative stress, and modulating calcium homeostasis, with these effects amplified by RXR activation. The VDR-RXR heterodimer interaction appears critical for enhancing transcriptional activity, promoting neuronal resilience, while potentially slowing neurodegeneration progression. We propose that combined vitamin D₃ and vitamin A supplementation could offer a promising therapeutic strategy by synergistically optimizing VDR-RXR signaling, thereby improving neuroprotection. This hypothesis requires validation through an integrated approach that includes molecular, cellular, behavioral, and translational neuroimaging methods to investigate neuroprotective effects associated with VDR-RXR co-activation.