Abstract
Collagen triple helix repeat containing 1 (CTHRC1) is a secreted extracellular matrix (ECM)-associated protein involved in tissue remodeling, fibrosis, and cancer, but its functions in the nervous system remain incompletely defined. Evidence from peripheral nerve, brain tumor, neurodegeneration, and regeneration models suggests that CTHRC1 may exert context-dependent effects across neural and stromal cell populations. In Schwann cells, CTHRC1 regulates proliferation, migration, and the timing of myelination, whereas in glioma it promotes invasive behavior and treatment-resistant phenotypes. Human cortical proteomics, mouse-model studies, systems genetics, and a neuronal cell model associate CTHRC1 with Alzheimer's disease-related phenotypes, although bulk tissue does not identify the cellular source and a small cerebrospinal fluid cohort showed no significant change. Temporally resolved single-cell analysis in zebrafish identified a transient cthrc1a-expressing fibroblast state required for coordinated inflammatory dynamics during regeneration; an equivalent mammalian mechanism has not been established. Evidence connecting CTHRC1 to synaptic regulation, neuroprotection, Parkinson's disease, and cerebrovascular repair is still preliminary. Wnt, TGF-β/Smad, PI3K/AKT, and MAPK/ERK pathways provide candidate mechanisms, but many were characterized outside normal neural cells. This review critically evaluates the evidence by model and cell type and discusses biomarker and therapeutic prospects, including delivery, specificity, and safety constraints.