Dimethyl malonate preserves brain and neurobehavioral phenotype following neonatal hypoxia–ischemia by inhibiting FTH1-mediated ferritinophagy

作者：Yiming Jin, Xinxin Wang, Xiaowen Xu, Xiuwen Zhou, Qing Wang, Li Zhang, Lili Li, Meifang Jin, Hong Ni · 发表于：Redox Biology · 年份：2025 · DOI：10.1016/j.redox.2025.103792 · 被引用次数：6 · 研究领域：Ferroptosis and cancer prognosis、Autophagy in Disease and Therapy、Neonatal and fetal brain pathology

Hypoxic–ischemic brain damage (HIBD) is a predominant cause of neuronal injury and mortality in newborns. Current preventive and therapeutic interventions demonstrate limited clinical efficacy. Emerging evidence reveals ferroptosis as a critical mechanism within HIBD pathophysiology, positioning it as a promising therapeutic target. Dimethyl malonate (DMM), a competitive inhibitor of succinate dehydrogenase, has demonstrated neuroprotective properties across multiple models of neurological disorders. However, the impact of DMM on the neonatal HIBD has not been studied. To investigate the neuroprotective effects of DMM against neonatal HIBD and elucidate its mechanisms of action. We created a model of HIBD in neonatal male C57BL/6J mice and administered various doses of DMM or vehicle control. Quantitative assessments included cerebral infarct volume measurement, Nissl staining for neurons, neurological behavior, ferrous ion (Fe 2+ ), malondialdehyde (MDA) level, 4-hydroxynonenal (4-HNE) expression, and solute carrier family 7 member 11 (SLC7A11, system Xc − )/glutathione peroxidase 4 (GPX4) antioxidant axis expression level. Parallel studies in vitro employed oxygen-glucose deprivation/reperfusion-treated HT22 cells to investigate the effects of DMM on ferroptosis and its underlying mechanisms. Moreover, key factors of ferritinophagy, including nuclear receptor coactivator 4 (NCOA4), SQSTM1/p62, ferritin heavy chain 1 (FTH1), and microtubule-associated protein light 3 II (LC3...