Atractylenolide III for central nervous system disorders: a review of multi-target mechanisms and therapeutic potential.

Central nervous system disorders (CNSDs) are a leading cause of global mortality and disability, yet treatment options remain limited. Natural compounds derived from traditional Chinese herbs constitute a vital resource for discovering novel neuroprotective agents. Atractylenolide III (ATL-III), a sesquiterpene lactone isolated from the spleen-fortifying herb Atractylodes macrocephala Koidz., exhibits neuroprotective properties and possesses the ability to cross the blood-brain barrier (BBB). However, a systematic summary of its effects on CNSDs is currently lacking. This review therefore aimed to comprehensively summarize the therapeutic effects and underlying mechanisms of ATL-III against various CNSDs, and to provide insights for future clinical translation. A systematic literature search was conducted using PubMed, Web of Science, Google Scholar, China National Knowledge Infrastructure, and Wanfang Database for studies published or available online between 1 January 2016, and 31 December 2025. The compiled evidence demonstrates that ATL-III is effective in preclinical models of cognitive impairment, cerebral ischemia/reperfusion injury, depressive disorder, and spinal cord injury. Its neuroprotective mechanisms are multifaceted, involving the enhancement of neurotransmitter storage, reduction of neurotoxic protein accumulation, and exerting anti-apoptotic, anti-inflammatory, antioxidant, and autophagy-regulating effects, alongside BBB repair. In conclusion, ATL-III exerts broad neuroprotective effects through multi-target mechanisms, highlighting its promise as a therapeutic candidate for CNSDs. To realize this potential, key future efforts should include: (1) conducting definitive clinical trials to establish its efficacy and safety profile; (2) comprehensively elucidating its pharmacological and toxicological properties; and (3) developing novel delivery strategies to enhance its bioavailability, BBB penetration, and brain retention.