ELAVL1 Stabilizes HMOX1 mRNA to Drive Ferroptosis in Diabetic Retinopathy.

OBJECTIVE: 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.