The Role of High Cxcl11 Expression in Ovarian Dysfunction Through NF‐κB and AKT Pathways in a Thin Endometrium Mouse Model

Objective Thin endometrium (TE) is a recognized cause of female infertility, primarily associated with impaired uterine receptivity. However, the potential impact of an impaired endometrial environment on distant ovarian function remains largely unexplored. Methods Ovarian changes were investigated in a mouse model of TE. Ovarian function was assessed by follicular counts and anti‐Müllerian hormone levels. Cytokine profiling was conducted using a Bio‐Plex Pro Mouse Chemokine 31‐Plex Panel. Protein interaction network analysis and Western blotting were employed to identify associated pathways. Ovarian macrophage polarization was evaluated, and in vitro ovarian cultures were treated with recombinant Cxcl11 alone or in combination with a neutralizing antibody. Results Compared with normal controls (NC), TE mice exhibited significant ovarian dysfunction, including reduced follicular numbers and lower anti‐Müllerian hormone levels (all p < 0.05). Cxcl11 was identified as a key upregulated factor. Cxcl11‐associated proteins were enriched in the NF‐κB/AKT pathway, and Western blot analysis confirmed activation of this pathway in TE ovaries. Ovarian macrophages in TE mice were skewed toward a pro‐inflammatory M1 phenotype, with a marked increase in INOS‐positive cells ( p < 0.0001). In vitro, recombinant Cxcl11 recapitulated NF‐κB/AKT pathway activation, whereas neutralization of Cxcl11 attenuated these effects (all p < 0.05). Conclusion TE is associated with impaired ovarian function in addition to defective endometrial receptivity. Mechanistically, Cxcl11 upregulation may promote ovarian macrophage polarization through the NF‐κB/AKT pathway, thereby contributing to ovarian dysfunction. These findings reveal a previously unappreciated link between uterine pathology and ovarian impairment and identify Cxcl11 as a potential target for fertility preservation.