HTRA1 is a serine protease with diverse extracellular and intracellular functions. As a serine-type endopeptidase, it degrades multiple extracellular matrix proteins including fibronectin, proteoglycans (aggrecan, decorin, fibromodulin), and fibrillar tau 1. HTRA1-generated fibronectin fragments stimulate synovial cells to upregulate MMP1 and MMP3 production. The protease regulates growth factor signaling by cleaving IGF-binding proteins and inhibiting TGF-β family signaling; loss-of-function mutations show decreased protease activity and failed TGF-β repression 2. Intracellularly, HTRA1 degrades TSC2, activating downstream targets, and can disaggregate α-synuclein amyloid fibrils in a protease-independent manner 1. HTRA1 mutations cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) and contribute to autosomal dominant cerebral small-vessel disease 23. In large population studies, HTRA1 carriers show increased stroke risk and all-cause dementia risk (OR 2.17) 4, with distinct blood-brain barrier dysfunction patterns including both elevated gadolinium leakage and reduced water exchange rates 5. HTRA1 also operates in tumor-immune suppression, where tumor-derived extracellular vesicles carrying HTRA1 upregulate MMP-13 in osteoprogenitors, disrupting hematopoiesis 6.