FAHD1 prevents neuronal ferroptosis by modulating R-loop and the cGAS-STING pathway.

Background: Ferroptosis, a type of iron-dependent lipid peroxidation-induced neuronal death, has been strongly implicated in the initiation and progression of various neurological disorders, including neurodegenerative diseases and central nervous system (CNS) injuries. Although significant research efforts have been devoted to this area, most available therapeutic strategies remain largely ineffective due to the complex pathophysiology of these conditions. Moreover, the mechanisms underlying neuronal ferroptosis are not yet fully elucidated. Methods: To investigate the role of FAHD1 in neuronal ferroptosis, bioinformatic analyses and cellular experiments were performed. Immunofluorescence and dot blot analyses were employed to explore the effects of FAHD1 overexpression on R-loop formation. Additionally, western blotting was used to assess alterations in the expression of cGAS-STING pathway-related proteins resulting from FAHD1 overexpression. Results: Our results demonstrate that FAHD1 expression is significantly downregulated in primary neurons subjected to oxidative stress. Furthermore, ferroptosis appears to be a major contributor to neuronal damage triggered by oxidative stress. Overexpression of FAHD1 significantly reduced reactive oxygen species accumulation and R-loop formation, preserved genomic stability, and suppressed neuronal ferroptosis by inhibiting activation of the cGAS-STING pathway. Conclusion: FAHD1 is a critical regulator of neuronal ferroptosis and may serve as a potential therapeutic target for the treatment of neurodegenerative diseases and CNS injuries.