Mechanistic insights into PM2.5-induced myopia in mice: Role of NRF2/HIF-1α signaling and therapeutic potential of sulforaphane.

Particulate matter 2.5 (PM2.5) has been implicated in the development of myopia. This study aimed to elucidate the molecular mechanisms through which PM2.5 exposure influences myopia progression. We integrated Mendelian randomization (MR) analysis of large-scale genetic data, revealing a significant association between particulate matter air pollution (PMAP) and myopia risk (OR = 1.065, 95 % CI: 1.033-1.098; P = 4.73× 10⁻⁵). In mice, ocular PM2.5 exposure induced pathological axial elongation, accompanied by suppression of NRF2 expression. Mechanistic investigations demonstrated that NRF2 directly binds to HIF-1α, inhibiting its transcriptional activity. Using CETSA, we identified sulforaphane as a selective NRF2 stabilizer that mitigates PM2.5-induced myopia progression in mice. These findings present genetic epidemiological evidence supporting a causal association between PMAP exposure and myopia, elucidate a molecular mechanism by which PM2.5 mediates oxidative stress via the NRF2/HIF-1α signaling axis, and identify sulforaphane as a potential therapeutic agent targeting NRF2, thereby offering novel strategies for the prevention and treatment of environmentally associated myopia.