Int J Biol Macromol. 2025 Nov 19:149102. doi: 10.1016/j.ijbiomac.2025.149102. Online ahead of print.
ABSTRACT
Cataracts seriously affect the vision of patients and can even lead to blindness. RAB3GAP2 is associated with cataracts, but its regulatory effects on cataracts need to be determined. We established a mouse model of cataracts and cell models of cataracts induced by NaIO3, to elucidate the exact function and molecular mechanism of RAB3GAP2 in cataract regulation. RAB3GAP2 was highly expressed in the lenses of a mouse model of cataracts. In cell models of cataracts, RAB3GAP2 silencing attenuated apoptosis and reactive oxygen species (ROS) production, intensified mitochondrial autophagy, relieved mitochondrial oxidative stress, and increased the mitochondrial membrane potential. These effects were eliminated by CsA treatment or Mfn2 silencing. We subsequently performed RNA sequencing analysis and experimental verification and found that RAB3GAP2 silencing activated JNK/STAT3 to increase the transcription of Mfn2. Further in vitro studies revealed that SP600125 treatment reversed the effects of RAB3GAP2 silencing on cataract development, the promotion of Mfn2 and mitochondrial autophagy, and the activation and nucleation of STAT3. Finally, in vivo, RAB3GAP2 silencing suppressed apoptosis and ROS production, increased Mfn2 expression and mitochondrial autophagy, and activated JNK/STAT3 and the nucleation of STAT3 in a mouse model of cataracts. However, these in vivo results were abrogated by SP600125 treatment. These findings suggest that RAB3GAP2 silencing can mitigate oxidative stress to prevent cataract development, probably by facilitating Mfn2-mediated mitochondrial autophagy by activating JNK/STAT3. It may be a promising target for treating cataracts.
PMID:41271057 | DOI:10.1016/j.ijbiomac.2025.149102