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

Particulate matter 2.5 (PM_2.5) has been implicated in the development of myopia. This study aimed to elucidate the molecular mechanisms through which PM_2.5 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 PM_2.5 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 PM_2.5-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 PM_2.5 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.