From risk factors to molecular targets: clinical associations and molecular docking insights into phthalate-associated diabetic retinopathy.

Objective: This study aimed to identify novel risk factors for diabetic retinopathy (DR) and to explore whether phthalate exposure contribute to DR pathogenesis. Methods: We analyzed data from the 2017-2018 National Health and Nutrition Examination Survey (NHANES) and an independent clinical cohort using multiple feature-selection methods. To investigate the potential mechanisms of di-2-ethylhexyl phthalate (DEHP), we performed network toxicology and molecular docking analyes. Results: In NHANES, longer weekday outdoor time was associated with higher odds of DR (OR = 3.18, 95% CI: 1.36-7.95), whereas higher serum epi-25-hydroxyvitamin D3 levels were associated with lower odds of DR (OR = 0.80, 95% CI: 0.64-0.97). In the clinical cohort, less electronic device use was correlated with lower odds of DR (OR = 0.67, 95% CI: 0.43-0.98), while cataract was strongly associated with DR (OR = 11.0, 95% CI: 1.77-99.8). Urinary phthalate assessment showed inverse associations of mono-isobutyl phthalate (MiBP) and a mixed phthalate index with DR. Network toxicology identified 123 overlapping target genes, with enrichment in AGE-RAGE signaling and apoptosis-related pathways. Molecular docking predicted stable binding of MiBP to SRC, BCL2, and MAPK1. Conclusion: This integrative analysis identifies novel clinical and environmental correlates of DR and suggests a possible link between phthalate exposure and DR-related pathways. These findings highlight the potential relevance of environmental exposures in DR risk and offer a basis for further mechanistic and preventive research.