Worldwide, cataracts remain the leading cause of irreversible blindness, primarily driven by age-related changes and free radical-mediated lens damage. Posterior capsular opacification (PCO) is a common complication following cataract surgery, arising from aberrant proliferation and epithelial-mesenchymal transition (EMT) of residual lens epithelial cells (LECs). The transforming growth factor-β (TGF-β)/Smad signaling cascade is among the most critical pathways underlying both cataractogenesis and PCO, as it drives EMT and subsequent fibrotic alterations. MicroRNAs have emerged as key regulators of ocular homeostasis, with miR-204-5p being particularly relevant. Highly expressed in the lens, miR-204-5p has been shown to target TGFBR2, a core component of the TGF-β/Smad pathway, and thereby suppress downstream signaling. Downregulation of miR-204-5p appears to enhance TGF-β signaling, which may contribute to lens fibrosis and opacification during cataract development or after surgery. This article reviews current understanding of the interplay between miR-204-5p and the TGF-β/Smad signaling pathway in LECs, focusing on their roles in EMT and fibrotic progression. We also highlight experimental evidence supporting miR-204-5p as a promising candidate for PCO prevention. Emerging evidence also suggests that miR-204-5p regulates oxidative stress and mitochondrial homeostasis through additional targets in lens epithelial cells, highlighting its broader therapeutic potential. Elucidating crosstalk between signaling and epigenetic regulation in LEC biology opens new avenues for non-surgical management of cataracts and PCO. This review underscores the need for further research into miRNA-mediated modulation of fibrotic signaling, establishing this as an innovative and promising direction in molecular ophthalmic therapy. not applicable. • miR-204-5p is a key regulator of TGF-β/Smad signaling in lens epithelial cells. • Downregulation of miR-204-5p promotes EMT and fibrosis in PCO. • miR-204-5p targets TGFBR2 and Smad4 to suppress fibrotic signaling. • miRNA-based strategies may provide non-surgical prevention of PCO.
Sadeghi et al. (Wed,) studied this question.