The HTRA1–Extracellular Matrix Axis in Health and Disease: From Pathological Remodeling to Therapeutic Opportunities in Fibrosis, Osteoarticular Disorders, and Cancer

High-temperature requirement A serine peptidase 1 (HTRA1) is a secreted serine protease that regulates extracellular matrix (ECM) homeostasis through direct proteolysis and indirect effects on matrix production and turnover. This review integrates evidence from fibrosis, bone and joint diseases, and cancer to examine how HTRA1 contributes to matrix remodeling and disease-associated cellular responses. In fibrosis, HTRA1 influences matrix accumulation by regulating collagen trafficking and secretion and transforming growth factor-β (TGF-β) signaling. In bone and joint diseases, HTRA1-mediated degradation of matrix components and induction of downstream proteases jointly contribute to tissue degeneration. In cancer, HTRA1 participates in tumor–stroma interactions through extracellular and intracellular mechanisms. Cross-disease comparison highlights the interplay between extracellular proteolysis, matrix production, and cellular signaling, alongside the tissue-dependent protective and pathogenic roles of HTRA1. We also summarize preclinical strategies for modulating HTRA1 and identify key gaps in current research. This review provides a conceptual framework for future mechanism-driven and translation-oriented research on HTRA1 in ECM-related diseases.