Objective <p>Posterior capsular opacification (PCO) is a significant complication that causes decreased vision in cataract patients after surgery. Epithelial-mesenchymal transition (EMT) and inflammation are key factors in PCO development. This study examined the protective effect of Micheliolide (MCL) in preventing PCO and its related mechanisms.</p> Methods <p>In vivo studies were conducted using an extracapsular lens extraction (ECLE) model combined with intracameral injection, while in vitro experiments utilized TGF-β2-induced EMT in lens epithelial cells (LECs). In vivo biological effects were assessed by TUNEL staining and alizarin red staining. The expression levels of EMT and inflammatory markers were analyzed by Western blotting, quantitative real-time PCR (qRT-PCR), and immunofluorescence. Hematoxylin-eosin (HE) staining, Transwell assays, and scratch wound healing assays were employed to evaluate the migratory and proliferative capacities of LECs.</p> Results <p>In both in vivo and in vitro experiments, MCL treatment significantly suppressed the inflammatory response, expression of EMT markers, and the proliferative and migratory capacities of LECs. To further elucidate the underlying mechanism, RNA sequencing was performed on capsular bags collected at 0 h, 24 h, and 5d post-ECLE. Transcriptomic analysis revealed that matrix metalloproteinase 8 (MMP8) was upregulated at 24 hours after surgery, and this induction was markedly attenuated by MCL administration. Consistent with these findings, in vitro studies demonstrated that combining MCL with an MMP8 inhibitor (M8I) synergistically suppressed the expression of EMT-related proteins in LECs.</p> Conclusion <p>Our research confirms the effectiveness of MCL in inhibiting PCO through anti-inflammatory and anti-fibrotic effects, and it exerts its mechanism of inhibiting EMT through MMP8. </p>