Auranofin reimagined: an emerging therapeutic candidate for neurodegenerative diseases through molecular mechanistic insights.

Drug repurposing presents a strategic shortcut in therapeutic discovery, especially in the complex landscape of neurological disorders where traditional drug development faces substantial challenges. A compelling candidate in this domain is auranofin (AF), an FDA-approved gold(I) compound initially indicated for rheumatoid arthritis, now gaining traction for its broad neuroprotective potential across multiple preclinical models, including Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic brain injury (TBI), and epilepsy. AF exerts multifaceted neuroprotective effects primarily through the Keap1–Nrf2–ARE pathway, which upregulates the expression of antioxidant and anti-inflammatory genes while suppressing the production of pro-oxidant and pro-inflammatory mediators. In AD, AF reactivates the PI3K/AKT axis, downregulates GSK-3β, and mitigates tau pathology. In TBI, it disrupts the ASK1–MAPK cascade, enhances mitochondrial integrity, and upregulates the anti-apoptotic protein Bcl-2. In PD, it promotes neuronal survival through the AKT–FOXO/CREB pathway, while in epilepsy, it attenuates neuroinflammation and oxidative stress via inhibition of NF-κB signaling. By orchestrating a multi-targeted neuroprotective response converging on Nrf2 signaling, AF emerges as a potential repurposing candidate with multi-pathway neuroprotective activity. Peer-reviewed data from Scopus, PubMed, and Web of Science support all findings. To our knowledge, this is the first comprehensive review to highlight AF multi-pathway activity in neurodegenerative disorders, addressing critical gaps in current knowledge. These preclinical insights collectively underscore its translational potential and capacity to reshape the neurotherapeutic landscape.