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.