Inhibition of NTF4 Attenuates High Glucose‐Induced Apoptosis and Inflammation in HTR‐8/SVneo Cells via the PI3K/AKT Pathway

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.