Obesity impairs endometrial mesenchymal stromal/stem-like cells function and decidualization via NF-κB signaling activation

Endometrial mesenchymal stromal/stem-like cells (eMSC) are essential for endometrial regeneration, receptivity, and decidualization during early pregnancy. Obesity, characterized by chronic metabolic and inflammatory disturbances, is strongly associated with subfertility. However, its impact on eMSC function and decidual differentiation remains poorly understood. This study investigated whether obesity-associated metabolic stress impairs eMSC biological function and decidualization through activation of the NF-κB signaling pathway, thereby potentially contributing to reduced endometrial receptivity and adverse reproductive outcomes. Endometrial tissues from non-obese and obese women were analyzed for apoptosis and receptivity markers using western blot and immunohistochemistry. First-trimester decidual tissues from both groups were evaluated for decidualization markers by quantitative PCR and immunohistochemistry. In vivo, female mice were fed a high-fat diet (HFD) or control diet (CON) for nine weeks, followed by mating to assess implantation outcomes and decidual responses. A label-retaining cell technique was employed to identify endometrial stem/progenitor cells in mice. In vitro, human eMSC isolated from endometrial tissues were exposed to palmitic acid (PA) to mimic obesity-associated metabolic stress. EMSC phenotypic expression, proliferation, migration, clonogenicity, self-renewal, and decidualization capacity were evaluated. RNA sequencing was performed to identify signaling pathways altered by PA exposure. NF-κB activation was assessed by quantitative PCR, western blot, and the NF-κB inhibitor Bay11-7082 was used to examine its mechanistic role. Obese women exhibited increased endometrial apoptosis and reduced expression of receptivity markers, along with markedly decreased decidual IGFBP1 and PRL expression. Similarly, HFD-induced obese mice showed impaired uterine receptivity, defective decidual transformation, and reduced implantation sites. Exposure to obesity-associated metabolic stress significantly impaired the proliferation, migration, clonogenicity, stemness-related properties, and decidualization capacity of eMSC in vitro. Transcriptomic and biochemical analyses suggested the involvement of NF-κB signaling in PA-induced eMSC dysfunction. PA-treated eMSC displayed enhanced NF-κB pathway activation, elevated pro-inflammatory cytokine expression, and increased oxidative stress. Pharmacological inhibition of NF-κB partially restored the impaired phenotype and decidualization capacity of PA treated eMSC and was associated with improved reproductive parameters in HFD mice. Our findings suggest that obesity-associated metabolic stress may contribute to impaired endometrial receptivity and decidualization by disrupting multiple biological properties of eMSC. Mechanistically, NF-κB signaling appears to be involved in this process, and pharmacological inhibition of NF-κB signaling partially restored eMSC function and improved reproductive outcomes in an obesity model. These findings provide insight into the potential role of eMSC dysfunction in obesity-associated endometrial abnormalities and highlight NF-κB signaling as a potential therapeutic target warranting further investigation. Not applicable.