Curcumin Alleviates Vascular Cognitive Impairment by Inhibiting Ferroptosis Through Regulating the SIRT1/Nrf2/HO-1 Pathway.

Vascular cognitive impairment (VCI) is a cognitive disorder caused by cerebral hypoperfusion due to cerebrovascular diseases, characterized by declines in learning and memory abilities. Iron metabolism imbalance and ferroptosis are critical pathological mechanisms underlying VCI. Curcumin (CURC), a polyphenolic compound derived from turmeric, exhibits neuroprotective effects through anti-inflammatory, antioxidant, and antiapoptotic pathways. The present study investigated the therapeutic potential of CURC in VCI by exploring its role in inhibiting ferroptosis. In vitro, oxygen glucose deprivation (OGD)-induced injury in HT22 cells was significantly alleviated by CURC treatment, as evidenced by improved cell viability, reduced apoptosis, and decreased oxidative stress markers (ROS, MDA). CURC also attenuated ferroptosis by lowering Fe2+ levels and modulating ferroptosis-related proteins (GPX4 and ACSL4). Mechanistically, CURC activated the SIRT1/Nrf2/HO-1 pathway, which was supported by both pharmacological inhibition and genetic knockdown of SIRT1 in HT22 cells. In vivo, CURC improved cognitive deficits in VCI rats, as shown by reduced neurological deficit scores and enhanced performance in the Morris water maze test. Histological analysis revealed that CURC improved hippocampal neuron structure and increased the number of morphologically intact neurons. CURC also reduced hippocampal Fe2+ levels and regulated ferroptosis-related proteins, effects that were abolished by a SIRT1 inhibitor. Overall, CURC alleviated VCI symptoms in association with attenuated oxidative stress, apoptosis, and ferroptosis, and inhibition of neuronal ferroptosis through the SIRT1/Nrf2/HO-1 pathway may represent an important mechanism underlying its neuroprotective effects, providing a potential therapeutic strategy for clinical VCI treatments.