HTRA4 is a placenta-specific serine protease that plays critical roles in trophoblast function and placental development 1. The protein forms trimeric complexes and exhibits proteolytic activity against substrates including XIAP, caspases 7 and 9, β-tubulin, and actin, suggesting involvement in apoptotic regulation 2. HTRA4 is essential for syncytialization, the process by which cytotrophoblasts fuse to form syncytiotrophoblast; BeWo cells lacking HTRA4 fail to undergo forskolin-induced syncytialization 3. The protease also regulates trophoblast invasion, proliferation, and epithelial-to-mesenchymal transition, with extracellular matrix components inducing its expression 4. HTRA4 is significantly upregulated in early-onset preeclampsia but not late-onset disease, with elevated serum levels correlating with adverse pregnancy outcomes and blood pressure 15. High HTRA4 concentrations cause endothelial dysfunction by disrupting tube formation and increasing permeability through alterations in junctional proteins 1. Conversely, reduced HTRA4 expression is associated with recurrent pregnancy loss and impaired trophoblast invasion 6. The reciprocal regulation between HTRA4 and HTRA1 at the maternal-fetal interface may contribute to placenta accreta spectrum pathogenesis 4.