SPON1 (spondin 1) is an extracellular matrix protein with multifaceted roles in tissue homeostasis and disease. Functionally, SPON1 promotes cell adhesion and neurite outgrowth in spinal cord and sensory neurons, and serves as a major factor for vascular smooth muscle cell function. Mechanistically, SPON1 operates through protein-protein interactions in the extracellular matrix and can signal via lipoprotein receptor 8 (LRP8) to activate TGF-β1 and promote collagen production 1. Disease relevance spans multiple conditions. SPON1 is a matricellular protein with causal evidence for involvement in heart failure development, identified through proteomic and Mendelian randomization analyses 2. In metabolic dysfunction-associated steatohepatitis (MASH), SPON1 is concurrently upregulated and more accessible in activated hepatic stellate cells, contributing to pathogenic extracellular matrix production 3. SPON1+ inflammatory monocytes promote lung cancer metastasis through collagen remodeling via LRP8/TGF-β1 signaling 1. Genetic variants in SPON1 (rs2697825) associate with postmenopausal osteoporosis risk and bone mineral density 4. Additionally, SPON1 is elevated in cerebrospinal fluid nearly 30 years before Alzheimer's disease symptom onset and associates with amyloid-β plaques 5, with plasma SPON1 elevation observed in AD and long COVID 67. Clinically, SPON1 represents a novel drug target candidate with causal disease involvement 8, offering potential therapeutic opportunities across cardiovascular, hepatic, oncologic, and neurodegenerative diseases.