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.