Histamine Regulates the Th1/Th2 Balance and Modulates Endometrial Stromal Autophagy Through the CXCL9/CXCR3 Pathway

Intrauterine adhesion (IUA) and endometrial fibrosis are common conditions that can lead to infertility. Histamine, a key regulator of immune responses, has been implicated in various fibrotic diseases. This study explored the role of histamine and TGF-β in regulating CXCL9/CXCR3 expression and autophagy, and how these factors contribute to IUA progression. The effects of histamine and TGF-β on endometrial cells and IUA were evaluated using a combination of in vitro and in vivo experiments. Western blot, qRT-PCR, and immunohistochemistry (IHC) were used to measure the expression of fibrosis-related markers (α-SMA, Vimentin, CXCL9, CXCR3), autophagy markers (LC3B, p62), and cytokines. Additionally, flow cytometry was used to analyze Th1/Th2 polarization, and Masson and H&E staining assessed tissue fibrosis in IUA models. TGF-β treatment upregulated CXCL9/CXCR3 expression and enhanced fibrosis, as shown by increased levels of α-SMA, Vimentin, and autophagy markers. Histamine further exacerbated these effects by activating the CXCL9/CXCR3 pathway and inhibiting autophagic flux. Inhibition of CXCL9 expression reduced fibrosis and improved angiogenesis in IUA models. Histamine treatment increased cytokine levels (IL-4, IL-6, IL-12, IFN-γ), while the HDC inhibitor reduced these cytokine levels and alleviated fibrosis. Histamine injection further aggravated fibrosis, while the HDC inhibitor reversed these changes. Histamine promoted IUA progression by activating the CXCL9/CXCR3 pathway and inhibiting autophagic flux. Targeting histamine or its signaling pathway may provide new therapeutic strategies for managing IUA and related fibrotic conditions.