Molecular mechanism of lanosterol binding to αB-crystallin for inhibition of UV-A induced aggregation

Recent studies have demonstrated that lanosterol modulates the aggregation of crystallins. However, the molecular mechanism by which lanosterol binds to crystallins remains incompletely understood. It is crucial to assess whether lanosterol can prevent the aggregation of crystallins under environmental and oxidative stress conditions. It is well-established that the aggregation of αB-crystallin induced by UV-A radiation contributes to the progression of lens opacity and cataract formation. In this study, the inhibitory potential of lanosterol against the aggregation of human αB-crystallin was investigated at the molecular level. Spectroscopic analysis revealed that lanosterol, at a concentration of 75 μM, exhibited the most significant suppression of αB-crystallin aggregation in vitro, preserving its secondary structure under UV-A exposure. Lanosterol undergoes a thiol-ene click reaction, thereby preventing the formation of disulfide bonds due to the oxidation of methionine residues in αB-crystallin. By contrast, in the ex vivo mouse lens model, a concentration as low as 50 µM lanosterol provided the optimal therapeutic effect in terms of lens transparency restoration and light transmission. Western blot analysis showed that lanosterol significantly increased αB-crystallin expression in the lens. Computational modeling further corroborated the experimental findings. These findings offer a novel molecular model for cataract treatment.

Cataract; Computational modeling; Lanosterol; Molecular mechanism; αB-crystallin.