ITGA11 regulates lens epithelial-mesenchymal transition by modulating PTGS2-mediated lipid metabolism.

PURPOSE: Anterior subcapsular cataract (ASC) is driven by lens epithelial cell (LEC) epithelial-mesenchymal transition (EMT), yet the upstream regulators and metabolic programs remain incompletely understood. This study aimed to identify key drivers of lens fibrosis and define their downstream signaling and metabolic mechanisms.

METHODS

Transcriptomic datasets from human ASC lens capsules and TGF-β2-induced LEC EMT models were re-analyzed, together with targeted lipidomic profiling. ITGA11 was silenced in LECs using siRNA, and PTGS2(COX-2) activity was inhibited using the COX-2 inhibitor celecoxib. RNA sequencing of ITGA11-silenced cells was performed to identify downstream pathways. EMT markers, cell migration, and signaling changes were assessed by RT-qPCR, Western blotting, immunofluorescence, and scratch assays.

RESULTS

ASC lenses exhibited EMT and focal-adhesion pathway activation. Integrin-mediated adhesion signaling was prominently upregulated, with ITGA11 identified as a highly induced integrin. Cross-model integration revealed ITGA11 as part of a conserved fibrosis gene signature shared across different lens EMT models. Functionally, ITGA11 knockdown impaired LEC migration and suppressed TGF-β2-induced myofibroblast transdifferentiation, reducing α-SMA and fibronectin expression. Mechanistically, ITGA11 depletion attenuated the induction of PTGS2, a key enzyme driving fatty acid metabolic reprogramming. Lipidomic profiling demonstrated a shift in arachidonic acid metabolism toward pro-inflammatory prostaglandins during EMT, consistent with engagement of a PTGS2-associated metabolic axis. Pharmacologic inhibition of PTGS2 suppressed EMT-associated phenotypes.

CONCLUSIONS

ITGA11 promotes lens fibrosis by driving PTGS2-related inflammatory lipid metabolism involved in LEC myofibroblast transdifferentiation.