Abstract:AIM: To determine whether paeonol (Pae), a naturally occurring phenolic compound, can serve as an effective pharmacological inhibitor of posterior capsular opacification (PCO). METHODS: A rat model of cataract surgery—induced PCO was established, and Pae was administered via anterior chamber injection to evaluate its preventive effect on capsular opacification and fibrotic remodeling. Histological and immunohistochemical analyses were performed to assess epithelial-mesenchymal transition (EMT)—related changes in lens epithelial cells (LECs). Ex vivo lens capsule cultures were employed to examine the expression of Vimentin and Zonula Occludens-1 (ZO-1) by immunofluorescence and immunohistochemistry. In the human LEC line SRA01/04, EMT marker expression at both mRNA and protein levels was analyzed following transforming growth factor beta 2 (TGF-β2) stimulation, with Pae treatment. Western blotting and immunofluorescence were used to investigate the effect of Pae on TGF-β/Smad signaling and AMP-activated protein kinase (AMPK) activation. Molecular docking was performed to predict Pae–AMPK binding, and rescue experiments with AMPK inhibition were conducted to validate the mechanistic pathway. RESULTS: Pae significantly reduced capsular opacification and fibrotic remodeling in the rat PCO model compared with controls. In LECs, Pae markedly suppressed TGF-β2–induced EMT, evidenced by decreased expression of mesenchymal markers, such as Vimentin, Fibronectin, Collagen 1A1, α-SMA and preserved epithelial junctional protein ZO-1. Mechanistically, Pae was predicted to directly interact with the catalytic pocket of AMPK, which was experimentally confirmed by enhanced AMPK phosphorylation and nuclear translocation (P<0.05). This activation disrupted canonical TGF-β/Smad signaling, leading to suppression of EMT. Rescue experiments using AMPK inhibition abrogated the anti-EMT effect of Pae, further validating the AMPK-dependent mechanism. CONCLUSION: Pae exerts a potent inhibitory effect on PCO formation by blocking EMT of LECs through direct activation of AMPK and subsequent disruption of TGF-β/Smad signaling.
