High-temperature requirement A serine peptidase 1 (HTRA1) (HTRA1)

High-temperature requirement A serine peptidase 1 (HTRA1) is a secreted trimeric serine protease belonging to the trypsin family, characterized by its unique domain structure including an IGFBP-like domain, a Kazal-like domain, a protease domain, and a PDZ domain [1, 5, 34]. It plays a critical role in maintaining tissue homeostasis by regulating the degradation of extracellular matrix (ECM) proteins and modulating signaling pathways such as TGF-beta, BMP, and Notch [1, 2, 4, 9]. HTRA1 is genetically linked to several major diseases; specifically, over-expression due to promoter polymorphisms is a primary risk factor for age-related macular degeneration (AMD) and geographic atrophy, while loss-of-function mutations cause the hereditary cerebral small vessel disease known as CARASIL [4, 7, 10, 16]. In oncology, HTRA1 acts as a context-dependent regulator, often functioning as a tumor suppressor by promoting apoptosis and inhibiting metastasis, though its downregulation is associated with poor prognosis in various cancers [1, 13, 14]. Therapeutic strategies primarily focus on inhibiting HTRA1's proteolytic activity in the eye to slow the progression of geographic atrophy, with several antibody fragments and small molecules having entered clinical and preclinical development [7, 10, 15, 22].

Other names

ARMD7HtrAHTRA1_HUMANIGFBP5-proteaseL56ORF480protease, serine, 11 (IGF binding)PRSS11serine protease HTRA1

HTRA1 inhibitors work by binding to the protease domain or allosterically locking the enzyme in an inactive conformation, thereby preventing the cleavage of extracellular matrix proteins and the dysregulation of TGF-beta signaling [7, 10, 29, 35].