HTRA1 and brain disorders: A balancing act across neurodegeneration and repair

High temperature requirement protein A1 (HTRA1) is a trypsin-like serine protease increasingly recognized as a central regulator of brain homeostasis. HTRA1 is broadly expressed in the brain, where it regulates proteostasis, extracellular matrix (ECM) remodeling, and important signaling pathways such as: TGF-β, Wnt, and Notch. These functions are essential for maintaining blood-brain barrier integrity, supporting tissue repair, and restraining inflammation. HTRA1 is a double-edged sword, as both insufficient and excessive activity can lead to neurodegenerative and vascular pathology. Reduced HTRA1 levels are linked to ECM accumulation and vascular fibrosis, while elevated activity contributes to tissue breakdown, inflammation, and impaired repair. This dual role is implicated in a range of disorders, including cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, small vessel disease, age-related macular degeneration, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. We review recent insights into HTRA1's interactions with ApoE and tau, its roles in lipid and cytoskeletal regulation, and its modulation by inhibitors such as: Macrophage Migration Inhibitory Factor. Finally, we explore its biomarker potential and therapeutic targeting strategies. Understanding the mechanisms behind HTRA1’s shift from protective to pathological is crucial for developing targeted therapies that preserve its beneficial roles. Created in BioRender. Hjæresen, S. (2025) https://BioRender.com/6amefnv . • HTRA1 serves as a central regulator of proteostasis and extracellular matrix dynamics. • Dysregulation of HTRA1 contributes to neurodegenerative and vascular pathologies. • HTRA1 modulates TGF-β, Wnt, and Notch signaling pathways in the CNS. • Interaction with ApoE links HTRA1 to Alzheimer’s disease and lipid metabolism. • HTRA1 emerges as a potential biomarker and therapeutic target in MS and AMD.