HTRA3 is a serine protease that functions as a multifaceted regulator of cellular homeostasis and tissue remodeling. As a serine endopeptidase, HTRA3 cleaves extracellular matrix components including decorin, biglycan, and fibronectin, and negatively regulates transforming growth factor-beta (TGF-β) signaling 1. The protein exists as two isoforms generated through alternative splicing: a long form with a PDZ domain and a short form lacking this domain 2. Structurally, HTRA3 forms trimers through PDZ domain-mediated interactions, though the PDZ domain is dispensable for proteolytic activity 3. Beyond ECM remodeling, HTRA3 interacts with cytoskeletal proteins including actin, tubulin, and vimentin, exhibiting chaperone-like co-chaperone activity 4. Clinically, HTRA3 demonstrates tumor suppressor functions across multiple cancer types. In cardiac tissue, pressure overload downregulates HTRA3 expression, permitting TGF-β signaling activation that drives both fibrosis and heart failure; HTRA3 overexpression ameliorates cardiac dysfunction 1. Conversely, HTRA3 is significantly downregulated in endometrial cancer, ovarian cancer, and head and neck squamous cell carcinoma, with reduced expression correlating with increased tumor grade and poor prognosis 5, 6, 7. In ovarian physiology, HTRA3 expression increases during folliculogenesis and luteinization, suggesting developmental roles 2. The loss of HTRA3 expression in malignancies combined with its pro-apoptotic and TGF-β-inhibitory functions positions it as a promising therapeutic target.