ELAVL1 Stabilizes HMOX1 mRNA to Drive Ferroptosis in Diabetic Retinopathy

Yanjun Gao,1 Wenjing Zhao,2 Qiannan Chai,1 Cunxi Ye1 1Department of Ophthalmology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China; 2Department of Hemodialysis, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of ChinaCorrespondence: Cunxi Ye, The Second Hospital of Hebei Medical University, No. 215. Heping West Road, Xinhua District, Shijiazhuang, Hebei, 050000, People’s Republic of China, Email [email protected]: This study aims to investigate the role of heme oxygenase 1 (HMOX1) in the pathogenesis of diabetic retinopathy (DR) and identify the RNA-binding protein embryonic lethal abnormal vision-like 1 (ELAVL1) as a novel regulator of HMOX1 mRNA stability driving ferroptosis, proposing ELAVL1 as a potential therapeutic target for DR.Methods: DR was modeled in vitro using high glucose (HG)-treated ARPE19 cells and in vivo via streptozotocin (STZ)-induced diabetic rats. Cell damage was assessed through measuring cell viability, oxidative stress markers, iron content, and ferroptosis-related protein expression. HMOX1 expression and its regulatory interaction with ELAVL1 were analyzed using RT-qPCR, immunohistochemistry, Western blotting, RNA-fluorescence in situ hybridization, and RNA immunoprecipitation. Functional roles were validated by gene knockdown or overexpression experiments.Results: HG stimulation induced ferroptosis-related damage and oxidative stress in ARPE19 cells and the retinas of DR rats, accompanied by a significant upregulation of HMOX1 expression (approximately 165% in vivo and 189% in vitro). Knockdown of either HMOX1 or ELAVL1 effectively suppressed ferroptosis and mitigated retinal degeneration.Conclusion: HMOX1 is critical for ferroptosis-mediated retinal damage in DR, and ELAVL1 promotes ferroptosis predominantly by stabilizing HMOX1 mRNA.Keywords: ELAVL1, HMOX1, diabetic retinopathy, streptozotocin, ferroptosis