Targeting sirtuins in neurological disorders: A comprehensive review

The sirtuin (SIRT) family is a group of seven conserved nicotinamide adenine dinucleotide-dependent histone deacetylases (SIRT1-SIRT7), which play crucial roles in various fundamental biological processes, including metabolism, aging, stress responses, inflammation, and cell survival. The role of SIRTs in neuro-pathophysiology has recently attracted significant attention. Notably, SIRT1-SIRT3 have been identified as key players in neuroprotection as they reduce neuroinflammation and regulate mitochondrial function. This review summarizes the latest research advancements in the role of the SIRT family in neurological diseases, mainly including neurodegenerative diseases, ischemia-related diseases, bleeding-related diseases, nervous system injury and other nervous system diseases, emphasizing their critical functions and associated signaling pathways, (e.g., AMPK/SIRT1/PGC-1α, AMPK/SIRT1/IL-1β/NF-κB, STAT2-SIRT4-mTOR, SIRT3/FOXO3α, and other signaling pathways in disease progression, particularly their protective roles in neurodegenerative diseases, ischemic injuries, and neural damage. Additionally, this review discusses progress in clinical studies targeting SIRT-specific small-molecule agonists and inhibitors. Further research on SIRTs may provide new insights into potential therapeutic strategies for the prevention and treatment of neurological disorders.