Placental Pathology and HTRA4‐Mediated Autophagic Flux Disruption in Selective Fetal Growth Restriction Types I and III: A Morphological and Transcriptomic Study

To examine placental histomorphological and ultrastructural features in normal monochorionic diamniotic (MCDA) and selective fetal growth restriction (sFGR) pregnancies and investigate high temperature requirement A4 (HTRA4)'s potential role in mediating pathology. Included normal MCDA, sFGR placentas of type I and type III. Placental terminal villi maturity and syncytiotrophoblast (STB) ultrastructural features were assessed by immunohistochemistry and transmission electron microscopy. RNA sequencing identified differentially expressed genes, validated by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Functional studies using HTRA4-overexpressing BeWo cells. Type III sFGR-S placentas exhibited the most pronounced structural defects among the groups, including: diminished terminal villous maturity (manifested by reduced microvessel density and β-HCG with thickened villous syncytial membrane), elevated STB autolysosomes, and placental lipid droplet accumulation. HTRA4 was identified as a significantly upregulated gene in sFGR-S placentas, with mRNA and protein levels highest in type III, and fold change significantly greater than in type I or normal MCDA. Functional experiments confirmed that HTRA4 overexpression impaired syncytialization, disrupted autophagic flux, and altered lipid metabolism. This study reveals significant terminal villous hypoplasia and STB dysfunction in sFGR type III. HTRA4 upregulation mediates these abnormalities and reflects disease severity.