FADS1 inhibition protects retinal pigment epithelium cells from ferroptosis in age related macular degeneration

Purpose: Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly individuals. Retinal pigment epithelium (RPE) Ferroptosis is a significant pathogenetic component in AMD. This study aims to elucidate the role and mechanisms of fatty acid desaturase 1 (FADS1) in Ferroptosis as well as AMD progression.

Methods: An integrated bioinformatics analysis based on the array of data from the GEO database was conducted to identify candidates involved in Ferroptosis during AMD. Subsequently, cellular and mouse models of AMD were developed using sodium iodate (NaIO₃) to confirm the altered expression of FADS1. After treatment with a FADS1 inhibitor, cell survival, lipid peroxidation, and indicators of AMD were assessed in vitro and in vivo models. Further, immunofluorescence, immunohistochemistry, and swept-source OCT imaging were performed to assess the impacts of pharmacological inhibition of transcription factor specificity protein 1 (Sp1) on FADS1 and Ferroptosis.

Results: FADS1 expression was upregulated in AMD patients and in vitro and in vivo models of AMD. Its pharmacological inhibition had decreased mitochondrial ROS formation, lipid peroxidation, and Ferroptosis as well as increased RPE cell function in ARPE-19 cells and C57BL/6J mouse models of AMD. Mechanistically, Sp1 was identified as a key transcription factor of FADS1. Moreover, Sp1 inhibition downregulated FADS1 expression consequently attenuating FADS1-mediated Ferroptosis as well as AMD phenotypes.

Conclusion: For the first time, we demonstrated that Sp1 regulates FADS1-mediated Ferroptosis in RPE cells. Our findings provide novel insights into the progression and treatment of AMD.

Age-related macular degeneration; FADS1; Ferroptosis; Sp1.