Ceramide synthase 6 induces mitochondrial dysfunction and apoptosis in hemin-treated neurons by impairing mitophagy through interacting with sequestosome 1.

Intracerebral hemorrhage (ICH) is a severe subtype of stroke linked to high morbidity and mortality rates. However, the underlying mechanisms of neuronal injury post-ICH remain poorly understood. In this study, we investigated sphingolipid metabolism alterations in neurons using lipidomics and explored the regulatory mechanisms involved. Western blot and live-cell imaging were applied to detect mitochondrial quality and mitophagy level. We found a significant upregulation of ceramide synthase 6 (CERS6)-related C16 ceramide biosynthesis after hemin treatment. Knockdown of CERS6 notably ameliorated mitochondrial dysfunction and reduced neuronal apoptosis. Additionally, impaired neuronal mitophagy was observed after hemin treatment, which was restored by CERS6 knockdown. Mechanistically, CERS6 impaired mitophagy by interacting with sequestosome 1, leading to mitochondrial dysfunction and neuronal apoptosis. Our study explored the relationship between ceramide metabolism and mitophagy in neurons, revealing the pro-apoptotic role of CERS6 while providing a potential therapeutic target for patients with ICH.