Uterine natural killer (uNK) cells play a pivotal role in promoting placental development and supporting maternal-fetal immune tolerance, primarily through cytokine regulation and growth factor production. While the importance of uNK cells in pregnancy is well-established, the mechanisms of their interactions with trophoblasts and contributions to various pregnancy complications remain incompletely understood. This review highlights recent advancements in understanding uNK cell functions, with a focus on cytokine production, growth factor secretion, and receptor-ligand interactions, particularly involving killer immunoglobulin-like receptors (KIR) and human leukocyte antigen-C (HLA-C). We explore how uNK cell dysfunction contributes to pregnancy complications, including preeclampsia, recurrent pregnancy loss, and placenta accreta spectrum (PAS) disorders, emphasizing their roles in immune tolerance and placental health. By detailing the distinct cytokine signaling pathways and functional subtypes of uNK cells, this review provides insights into their regulatory mechanisms essential for pregnancy maintenance. Additionally, we discuss emerging therapeutic strategies targeting uNK-trophoblast interactions and propose future research directions, including the development of non-invasive biomarkers and personalized interventions. This comprehensive review addresses critical knowledge gaps, aiming to advance research in reproductive immunology and guide therapeutic innovations in maternal health.

Pregnancy disorders, including preeclampsia (PE), placenta accreta spectrum (PAS), and chorioamnionitis (CAM), significantly threaten maternal and fetal health, arising from immune and trophoblast dysregulation within the placental microenvironment. Traditional approaches lack the ability to resolve the spatial organization of these interactions. Spatial profiling technologies such as spatial transcriptomics and proteomics enable high-resolution mapping of gene and protein expression within intact tissue architecture, uncovering disease-specific immune checkpoint alterations, trophoblast invasion patterns, and localized inflammatory responses. These spatial signatures not only advance mechanistic understanding but also reveal candidate biomarkers for early diagnosis and risk stratification, such as reduced PD-L1 expression in PE and excessive checkpoint upregulation in PAS and CAM. In addition, these findings highlight therapeutic opportunities, including immune checkpoint modulation tailored to the placental microenvironment. Looking ahead, integrating spatial profiling with multi-omics and longitudinal analyses will be critical for translating spatial discoveries into precision diagnostics and targeted therapies, ultimately improving maternal-fetal outcomes.

Pregnancy complications are associated with abnormal cytotrophoblast differentiation and invasion. Hydrogen peroxide (H2O2) is an important mediator of oxidative ischemia/reperfusion stress in the placenta. Lycium barbarum polysaccharides (LBP) have been demonstrated to counteract oxidative free radicals. The effects of LBP in trophoblast HTR8/SVneo cells injured with H2O2 were examined. A cell counting kit‑8 assay was performed to detect the effect of LBP at different concentrations on the proliferative ability of H2O2 injured trophoblast cells. Flow cytometry was used to determine the levels of reactive oxygen species (ROS), mitochondria membrane potential (MMP) disruption and apoptosis. Superoxide dismutase (SOD) activity and lactate dehydrogenase (LDH) leakage into the supernatant was detected by ultraviolet spectrophotometry. Reverse transcription‑quantitative polymerase chain reaction and western blot analysis were performed to detect the expression of apoptosis‑associated factors, including survivin, hypoxia inducible factor 1‑α (HIF1‑α), Bcl‑2 apoptosis regulator (Bcl‑2), Bcl‑2 associated X apoptosis regulator (Bax). The results revealed that LBP protected the proliferative ability of trophoblast cells injured with H2O2 in a dose‑dependent manner. LBP inhibited the oxidative stress induced by H2O2, by reducing ROS and LDH levels and increasing SOD activity. Additionally, LBP decreased MMP disruption and cell apoptosis induced by H2O2, by increasing the mRNA and protein expression of survivin, HIF1‑α and Bcl‑2 and decreasing Bax expression. Therefore, it was concluded that LBP protected human trophoblast cells from H2O2‑induced oxidative stress and cell apoptosis via regulation of apoptosis‑associated factor expression. It will provide a novel strategy for the treatment of pregnancy complications.