Multiomics Integration Prioritizes ZFP36L1 as a Candidate Susceptibility Gene Associated With Inflammatory and Angiogenic Pathways in Diabetic Retinopathy

Background Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes and a leading cause of blindness despite available therapies, underscoring the need for novel therapeutic targets. Methods Integrated multiomics analysis combining (1) exploratory single‐cell RNA sequencing of rat retinal tissues (three DRs vs. two controls), (2) Mendelian randomization (MR) using whole‐blood eQTL data and DR GWAS data (14,584 cases vs. 202,082 controls), and (3) supportive RT‐qPCR validation in peripheral‐blood clinical samples (30 DRs vs. 30 controls). Results (1) Genetic causality was as follows: MR analysis demonstrated ZFP36L1 as a novel DR risk gene (OR = 1.156, 95% CI = 1.054–1.269, p = 0.002), with significant upregulation in patient blood samples (p < 0.0001). (2) Inflammatory regulation was as follows: ZFP36L1 showed strong correlations with proinflammatory markers (TNF‐α and IL‐6) and immune cell infiltration (parainflammation and Tregs), while negatively correlating with B cells. (3) Pathway mechanisms were as follows: Functional enrichment analyses suggested potential links between ZFP36L1 and NF‐κB–related inflammatory signaling as well as TGF‐β–related angiogenic pathways. Despite its known VEGF mRNA destabilizing function, we observed a positive ZFP36L1–VEGF correlation (r = 0.180, p < 0.001), an unexpected finding under diabetic conditions. Conclusions ZFP36L1 is a candidate DR susceptibility gene whose genetically regulated expression in blood is associated with DR risk. Retinal single‐cell and pathway analyses provide supportive, hypothesis‐generating evidence that ZFP36L1 may be linked to inflammatory and angiogenic processes relevant to DR. Further retina‐specific and functional studies are required to determine whether ZFP36L1 directly regulates retinal inflammation or angiogenesis in human DR.