Inhibition of miR-1-3p alleviates intrauterine adhesion in rats by promoting autophagy and suppressing pyroptosis in endometrial epithelial cells through targeting Sirt3.

BACKGROUND AND PURPOSE: Intrauterine adhesion (IUA) is a prevalent gynecological disorder that causes infertility and recurrent miscarriage; however, effective treatments remain limited. This study aimed to elucidate the function of Sirt3 in IUA and explore its underlying molecular mechanisms. METHODS: A rat IUA model was established by simulating mechanical endometrial injury, and an in vitro model was induced by treating human endometrial epithelial cells (hEECs) with recombinant TGF-β1. The expression of miRNAs and key proteins was detected via RT-qPCR, Western blotting, immunohistochemistry, and immunofluorescence. Cytokine levels were measured via ELISA, and endometrial damage in rats was assessed by using hematoxylin and eosin (HE) and Masson staining. RESULTS: We observed significant Sirt3 downregulation in IUA. Sirt3 overexpression ameliorated endometrial damage and fibrosis in IUA rats, thereby suppressing the expression of epithelial-mesenchymal transition (EMT) markers (vimentin and N-cadherin) and fibrosis-related proteins (α-SMA and collagen I) while also restoring E-cadherin expression. The overexpression of Sirt3 could also promote autophagy in hEECs induced by TGF-β1 (which promotes the expression of LC3 and Beclin 1 and inhibits the expression of p62), inhibit pyroptosis (which suppresses the expression of caspase-1, NLRP3, GSDMD, and ASC), and downregulate the levels of IL-1β and IL-18. These effects were reversed by the autophagy inhibitor chloroquine or the pyroptosis activator nigericin. Further investigation revealed that miR-1-3p was upregulated in IUA and could directly target and negatively regulate Sirt3 expression. Treatment with miR-1-3p antagomir suppressed EMT and fibrosis in hEECs under TGF-β1 exposure; however, this effect was attenuated by concomitant Sirt3 knockdown. CONCLUSION: In summary, miR-1-3p promotes IUA progression by suppressing Sirt3-mediated autophagy and activating pyroptosis, thereby driving EMT and fibrosis. The findings of this research revealed that the key role of Sirt3 in inhibiting the progression of IUA provides a potential target for the development of disease intervention therapies.