Haixia Wen, Yinyu Zi, Zhuhe Liu, Yunmeng Bai, Jingfang Lin, Hao Wang, Haitao Wang, Bingtian Xu, Jigang Wang, Honghao Wang, Honghao Wang
Neuromyelitis optica spectrum disorder (NMOSD) is recognized as a form of astrocytopathy; however, the mechanisms underlying aquaporin (AQP)4-IgG-induced astrocytic dysfunction remain to be fully elucidated. Here, single-nucleus RNA sequencing revealed that astrocytic ferroptosis is observed in mouse models of NMOSD, accompanied by expression alterations of multiple ferroptosis regulators. The activation of ferroptosis in astrocytes was further confirmed in in vitro NMOSD models through increased intracellular Fe²⁺ levels, lipid peroxidation, malondialdehyde, and lactate dehydrogenase levels, alongside reduced glutathione levels. Moreover, a remarkable increase in inflammatory reactive astrocytes was observed both in vivo and in vitro during NMOSD pathology. Notably, acyl-CoA synthetase long-chain family member 4 (ACSL4) upregulation in astrocytes was validated in NMOSD models. AQP4-IgG-induced ACSL4 upregulation was reversed by early growth response 1 (Egr1) siRNA. Suppressing ACSL4 expression mitigated astrocytic ferroptosis, reduced reactive astrocytes, attenuated demyelination, and ultimately improved NMOSD prognosis in mice. These findings demonstrate that ACSL4 mediates astrocytic ferroptosis, thereby contributing to NMOSD progression. Targeting ACSL4 may represent a promising astrocyte-directed therapeutic strategy for NMOSD.