Abstract

Objective This study aims to investigate the role of neurotrophin‐4 (NTF4) in gestational diabetes mellitus (GDM) and to elucidate the underlying mechanism by which NTF4 regulates high glucose‐induced apoptosis and inflammation in HTR‐8/SVneo cells via the PI3K/AKT signaling pathway. Methods Transcriptomic analysis combined with public database screening revealed that NTF4 is significantly upregulated in placental tissues from GDM patients. In a high glucose‐induced HTR‐8/SVneo cell model, NTF4 was silenced using small interfering RNA to evaluate the effects on cell proliferation, apoptosis, and inflammatory responses. Cell proliferation was evaluated using the CCK‐8 assay, apoptosis by flow cytometry, inflammatory cytokine secretion by ELISA, and cell migration and invasion by Transwell assays. Western blotting was performed to detect protein levels. Additionally, the PI3K‐specific inhibitor LY294002 was used to determine the pathway dependence of NTF4‐mediated effects. Results: NTF4 is upregulated in GDM placentas and high glucose‐induced HTR‐8/SVneo cells. Knockdown of NTF4 significantly ameliorated high glucose‐induced cell damage by enhancing cell viability, suppressing apoptosis, and inflammation. Mechanistic investigations revealed that NTF4 contributes to cellular injury by activating the PI3K/AKT signaling pathway, while the PI3K inhibitor LY294002 further amplified the protective effects of NTF4 silencing. Conclusions This study identified the role of NTF4 in promoting trophoblast injury by activating the PI3K/AKT signaling pathway in high‐glucose‐stimulated HTR‐8/SVneo cells, which provides a preliminary experimental basis for exploring its potential role in the pathogenesis of GDM.