Deep inside every chronically failing kidney, a quiet molecular drama unfolds. Scar tissue slowly strangles the delicate architecture of the nephron, replacing working tubules and capillaries with a dense, collagen-riddled matrix that can no longer filter blood. This process, renal fibrosis, is the common endpoint of nearly all forms of chronic kidney disease, and it is the reason millions of people progress toward dialysis and transplantation each year. Now a comprehensive review published in Molecular Biology Reports by an international team of researchers from Kazakhstan and the United Kingdom has pulled together the scattered evidence on a single secreted protein, collagen triple helix repeat containing 1, better known as CTHRC1, and argued that this molecule could be both a window into the fibrotic process and a lever for manipulating it.
CTHRC1 first caught the attention of vascular biologists in the mid-2000s, when it was discovered as a novel secreted protein produced in injured and diseased arteries, where it appeared to inhibit collagen expression while promoting cell migration. That combination of properties, simultaneously antifibrotic and promigratory, has haunted the literature ever since, because it hints at a molecule that does not simply push fibrosis forward or hold it back, but rather rewires the repair response itself. The new review, led by Gulzhan Bolebay and Askhat Myngbay of K. Zhubanov Aktobe Regional University together with Nikki A. Copeland and John G. Hardy of Lancaster University, systematically assembles what is known about CTHRC1 across organs, from arteries and bone to lungs, heart, liver, and skin, and then asks what this means for the kidney specifically.
The structural biology of CTHRC1 goes a long way toward explaining its versatility. The gene sits on human chromosome 8q22.3 and encodes several isoforms that differ in molecular weight and intracellular location. Secreted forms undergo posttranslational glycosylation before leaving the cell, which makes them heavier than their intracellular counterparts. The mature protein carries three functional regions: an N-terminal hydrophobic signal peptide of roughly twenty to thirty amino acids that directs the polypeptide into the secretory apparatus, a central collagen-like domain built from characteristic Gly-X-Y repeats that drive oligomerization, and a highly conserved C-terminal domain of about two hundred amino acids whose folds, according to structural modeling, resemble the C1q family and the noncollagen domains of collagens involved in building extracellular networks. Crucially, CTHRC1 can self-assemble into dimers and trimers, higher-order structures that stabilize the protein in the extracellular environment and increase its affinity for matrix components, properties that underpin its role in cellular locomotion and tissue remodeling.
Where CTHRC1 becomes truly interesting, and genuinely controversial, is in its relationship with transforming growth factor beta, the master conductor of fibrogenesis. TGF-beta1 is a secreted homodimeric protein that initiates the canonical T-betaRII-ALK5-Smad2/3 cascade in most cell types, driving myofibroblast activation, epithelial-mesenchymal transition, and the relentless accumulation of collagen and fibronectin that defines progressive scarring. Persistent inflammation hyperactivates this cascade, and TGF-beta also induces the noncanonical PI3K-AKT-mTOR pathway, amplifying the fibrotic transcriptional program. The review highlights that the CTHRC1-TGF-beta interaction is not unidirectional but tissue- and cell-type-dependent. In vascular smooth muscle cells, activation of the TGF-beta/Smad pathway increases CTHRC1 expression, while elevated CTHRC1 in turn reduces Smad2/3 phosphorylation and collagen synthesis, forming what looks like a negative feedback brake. Transgenic mouse studies showed that enhanced Smad2/3 phosphorylation induces CTHRC1 mRNA and protein, and that CTHRC1 overexpression suppresses TGF-beta signal transduction by lowering phosphorylated Smad2/3 levels. In experimental pulmonary fibrosis, CTHRC1 deficiency was accompanied by increased TGF-beta/Smad activity and excessive collagen deposition. Yet in hepatic stellate cells, the story flips: autocrine CTHRC1 enhances their activation, migration, and contractility through TGF-beta and noncanonical Wnt signaling, actively promoting liver fibrosis.
This context-dependence is the review’s central warning. The profibrotic or antifibrotic effects of CTHRC1 depend on the cellular and tissue environment, which means that mechanisms identified in arteries, lungs, or liver cannot be directly extrapolated to the kidney until confirmed by kidney-specific functional studies. What gives the renal question its particular shape is the expression pattern of CTHRC1 in kidney tissue: the protein is highly expressed in tubular cells and essentially undetectable in glomerular cells, providing a structural basis for investigating its association with tubulointerstitial injury, the histological signature that correlates most strongly with declining renal function. The review’s proposed model, illustrated in schematic figures, suggests that injured proximal tubular epithelial cells activate TGF-beta/Smad signaling and secrete CTHRC1, and that elevated concentrations of the protein in the tubulointerstitial area then initiate Wnt signaling on resident fibroblasts, transforming them into collagen-producing myofibroblasts.
That second arm of the model rests on CTHRC1’s role as a matricellular ligand in the assembly of Wnt signaling complexes. Coculture immunoprecipitation experiments showed that CTHRC1 binds directly to Wnt ligands and to the receptor Ror2, stabilizing the Wnt-receptor complex. In developmental contexts, CTHRC1 selectively activates the planar cell polarity pathway of Wnt signaling while suppressing the canonical Wnt/beta-catenin branch. But in fibrotic settings, the review argues, CTHRC1 can amplify multiple steps of the Wnt cascade, including ligand stabilization, receptor activation, inhibition of the beta-catenin destruction complex, and transcriptional activation of Wnt target genes, thereby driving profibrotic gene expression and extracellular matrix accumulation. Wnt signaling itself has deep renal roots: during embryonic kidney development, the ligands Wnt9b and Wnt4 are key initiators of the intracellular signals that transition nephrogenic mesenchymal cells into the epithelial cells that form nephrons, and the pathway continues to play roles in regeneration and renewal of adult tissues. The same developmental machinery, reawakened in adult injury, can become a scar-forming engine.
Evidence from other organs shows how powerful CTHRC1-positive fibroblast populations can be. Single-cell transcriptomic studies and lineage tracing in idiopathic pulmonary fibrosis identified a subpopulation of lung fibroblasts that produce the pathological extracellular matrix underlying fibrogenesis, localized in fibroblast foci, with high expression of matrix proteins. In bleomycin-induced lung fibrosis experiments, Cthrc1 knockout mice showed higher levels of TGF-beta and hydroxyproline, increased numbers of pSmad2-positive cells, beta-catenin activation in remodeling zones, and markedly decreased lung compliance compared with controls, indicating a protective role for CTHRC1 in limiting collagen formation. Patients with IPF exhibited notably elevated serum CTHRC1 levels that correlated with disease severity, and dynamic monitoring suggests that circulating CTHRC1 may reflect the activity and accumulation of pathological fibroblasts in lung tissue, making it a candidate prognostic biomarker. In the heart, single-cell RNA sequencing after myocardial infarction revealed a unique CTHRC1-high fibroblast population involved in ventricular remodeling and scar formation, a finding confirmed in preclinical pig models and in patients. A large-scale single-cell analysis spanning heart, lung, liver, and kidney fibrosis described a myofibroblast subtype designated CTHRC1_MyoFib as one of the populations with the highest expression of collagen genes, supporting the association of CTHRC1 with fibrotic matrix-forming cells across organs.
For the kidney specifically, the human evidence is real but thin. In the authors’ previous clinical study, plasma CTHRC1 levels were significantly higher in chronic kidney disease patients than in healthy controls and correlated with renal function markers including twenty-four-hour proteinuria, creatinine, urea, uric acid, and estimated glomerular filtration rate, suggesting that circulating CTHRC1 could serve as a valuable adjunct biomarker in CKD diagnosis. A search of ClinicalTrials.gov, the WHO ICTRP, EU Clinical Trials/CTIS, and the Cochrane Kidney and Transplant register found no active interventional trials targeting CTHRC1 in renal fibrosis, CKD, or diabetic kidney disease, meaning that clinical translation in nephrology remains in its earliest stages. Human tissue data exist mainly for renal cancers: CTHRC1 expression is elevated in kidney renal clear cell carcinoma and papillary cell carcinoma tissues, associated with tumor stage, lymph node metastasis, poor prognosis, and immune cell infiltration, and high expression predicted shorter survival in Wilms tumor cohorts examined by immunohistochemistry across forty-two tumor tissues and forty-two adjacent non-tumorous tissues. Proteomic analysis of mesothelial exosomes from children with focal segmental glomerulosclerosis on peritoneal dialysis identified CTHRC1 as a component of a protein profile associated with fibrosis and epithelial-mesenchymal transition. But the review is explicit that cancer pathogenesis and fibrosis pathogenesis are not the same, and that these findings cannot be directly extrapolated to renal scarring.
The most promising experimental frontier may be kidney organoids. Human induced pluripotent stem cell-derived organoids are being actively used to model fibrotic kidney disease: TGF-beta1 induction drives resident fibroblasts into myofibroblasts, upregulates fibrosis-related genes, and alters chromatin accessibility through a SMAD3-EZH2 axis, while other models reproduce phenotypes resembling human renal fibrosis, including tubular atrophy, glomerulosclerosis, and interstitial fibrosis, with RNA-seq revealing alterations in epithelial-mesenchymal transition, inflammation, metabolism, and JAK/STAT signaling. Inhibition of the kinase PIM1 attenuated fibrotic changes in organoids, and the bile acid receptor agonist INT-767 reversed TGF-beta1-mediated fibrogenesis by regulating p-SMAD3, TAZ/TEAD, and COL1A1. Yet most of these organoid studies have not specifically analyzed CTHRC1 as a key molecule, leaving the question wide open. The review proposes three concrete next steps: reanalyze published kidney organoid RNA-seq and single-cell RNA-seq data, comparing CTHRC1 expression with fibrosis markers such as COL1A1, COL3A1, FN1, ACTA2, POSTN, VIM, and TGFB1; examine CTHRC1 in organoids induced by TGF-beta1 or hypoxia and IL-1beta by qPCR, immunostaining, and ELISA; and functionally evaluate its effects on matrix formation, myofibroblast activation, and tubular injury through knockdown or overexpression. Initiatives such as the Kidney Precision Medicine Project, which aims to build molecular atlases of CKD and AKI, will allow future evaluation of CTHRC1 as a cellular-spatial biomarker of renal fibrosis.
The bottom line, as the review’s conclusion makes clear, is that CTHRC1 may be a promising biomarker for tissue damage and specific functional states of fibroblasts, but its precise role as a direct enhancer of renal fibrosis, a feedback regulator limiting the fibrotic process, or a therapeutic target remains unresolved. Its effects vary depending on cell type, tissue microenvironment, and disease stage, and may be contradictory in some cases, which makes elucidating its context-dependent functions a prerequisite for any safe therapeutic regulation of its activity. There are currently no specifically approved antifibrotic drugs that directly reverse renal fibrosis; existing treatment strategies, from renin-angiotensin-aldosterone system inhibitors to SGLT2 inhibitors and mineralocorticoid receptor antagonists, slow the decline in renal function but only indirectly inhibit fibrotic processes. If CTHRC1 levels show a consistent relationship with fibrosis severity, renal function decline, and disease progression in well-characterized patient cohorts, the protein could be used to stratify patients by risk and monitor treatment efficacy, and antifibrotic approaches targeting it could open genuinely new treatment strategies, provided their safety, efficacy, and renal selectivity are thoroughly investigated before entering the clinic. The scar-forming machinery of the kidney has finally been given a name worth watching.
Subject of Research: Potential role of CTHRC1 in renal fibrosis
Article Title: Potential role of CTHRC1 in renal fibrosis
Article References: Bolebay, G., Ayekenova, R., Izimova, R., Sarimbayeva, B., Shegenov, G. A., Mukhtarkhanovna, A. K., Issimov, A., Myngbay, A., Copeland, N. A., Amanbayeva, M., & Hardy, J. G. (2026). Potential role of CTHRC1 in renal fibrosis. Molecular Biology Reports, 53(1), Article 1740. https://doi.org/10.1007/s11033-026-12886-5
Image Credits: AI Generated
DOI: 10.1007/s11033-026-12886-5
Keywords: Potential, role, CTHRC1, renal, fibrosis, scientific research
News Source: Drew Townsend. (October 17, 2026). Potential role of CTHRC1 in renal fibrosis. Scienmag.
