SREBP1-driven SCD1 protects retinal pigment epithelium from oxidative damage by activating the NRF2/GPX4 axis.

Xingyu Yang, Weichen Xu, Hang Xie, Xiaoyu Guo, Feiyan Zhu, Yiqiao Xing, Changzheng Chen

Eye Center, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei, China; Eye Institute of Wuhan University, Hubei, China.Eye Center, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei, China; Eye Institute of Wuhan University, Hubei, China. · pubmed

Paper

Abstract

This study reveals the pivotal role of the Sterol Regulatory Element-Binding Protein 1 (SREBP1)/Stearoyl-CoA Desaturase 1 (SCD1) lipid metabolic axis in protecting retinal pigment epithelium (RPE) against oxidative damage. We demonstrate SCD1 downregulation in age-related macular degeneration (AMD) patient tissues and sodium iodate (SI)-induced models, while its overexpression enhances cell viability and ameliorates oxidative injury. Mechanistically, we uncover a novel pathway where SCD1-derived oleic acid activates the nuclear factor erythroid 2-related factor 2 (NRF2)/glutathione peroxidase 4 (GPX4) signaling cascade, scavenging reactive oxygen species (ROS) and suppressing lipid peroxidation. Notably, oleic acid also mitigated oxidative stress via this pathway without directly promoting cell survival. These results not only elucidate SCD1's crucial protective mechanism in AMD pathogenesis but also establish the SREBP1/SCD1 axis as a promising therapeutic target for developing innovative interventions against retinal degeneration.

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Research summary

The paper claims that SCD1-derived oleic acid activates the NRF2/GPX4 signaling cascade to protect retinal pigment epithelium from oxidative damage. This research is relevant as it addresses a mechanism related to oxidative stress in age-related macular degeneration, which is a significant aspect of aging and its associated diseases.

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