CHI3L1, also known as breast regression protein 39 in mice and YKL-40 in humans, belongs to the glycoside hydrolase 18 family and is categorized as a non-enzymatic chitinase-like protein. In humans, CHI3L1 is encoded by the CHI3L1 gene located on chromosomes 1q31-1q32. The gene consists of 7,498 base pairs and 10 exons, with genomic DNA that is ~8 kbp in length (14). The name ‘YKL-40’ reflects the molecular weight of the protein, at ~40 kDa, and the presence of the first three amino acids in the N-terminal sequence; namely, tyrosine (Y), lysine (K) and leucine (L) (15,16). Crystal diffraction studies revealed that CHI3L1 contains two distinct domains; namely, a (β/α)8-barrel domain, with a carbohydrate binding cleft of ~43 amino acids at the end of the β chain, and a second domain composed of an α helix and six inverted parallel β strands (17). This structural analysis suggested that CHI3L1 interacts with heparin and different cytokines, such as interleukin-13 receptor α2 (IL-13Rα2), CD44 (18). Despite its ability to bind to chitin, CHI3L1 lacks chitinase activity due to mutations in two critical catalytic residues, rendering it incapable of breaking down chitin or any other carbohydrates (19,20). CHI3L1 is secreted by various cell types, including macrophages, neutrophils, chondrocytes, synoviocytes, osteoblasts and smooth muscle cells (SMCs) (15). Although the specific function of CHI3L1 remains to be elucidated, this protein has been implicated in various biological processes, including cell proliferation, tissue remodeling, extracellular matrix (ECM) turnover, inflammation and fibrosis (21).

CHI3L1 is closely associated with inflammation and regulates the occurrence of inflammatory responses (22). A previous study using CHI3L1-/-mice revealed that CHI3L1 promoted the activation and enrichment of CD4+T cells and macrophages, subsequently regulating the TH2 inflammatory response. In addition, CHI3L1 promotes the production of the TH2 inflammatory factor, IL-13 (23). In addition, CHI3L1 induced macrophages to secrete monocyte chemotactic protein-1 (MCP-1), C-X-C motif chemokine ligand 2 (CXCL2), matrix metalloproteinase 9 (MMP-9) and other pro-inflammatory factors, promoting tumor growth and metastasis in a mouse model of breast cancer (24). In addition to promoting the production of inflammatory cytokines, CHI3L1 acts as an inflammatory target molecule that is regulated by a variety of other cytokines and hormones (25). For example, inflammatory factors; namely, TNF-α and IL-1, induce the expression of CHI3L1 in chondrocytes through the NF-κB signaling pathway (26,27). Thus, CHI3L1 demonstrates potential as a biomarker and therapeutic target. In Alzheimer's disease, the level of CHI3L1 in cerebrospinal fluid (CSF) is considered a biomarker of early neuroinflammation, which may be indicative of stress-induced neurotoxicity (28,29). CHI3L1 is also associated with the degree of liver inflammation and fibrosis; thus, exhibiting potential as a therapeutic target (10).

Type 2 diabetes mellitus (T2D), caused by obesity and insulin resistance, is characterized by abnormal lipid metabolism, which effects the occurrence of cardiovascular disease (30,31). Clinical data suggests that obese patients with T2D exhibit elevated CHI3L1 serum levels (Fig. 1) (32). Notably, elevated CHI3L1 levels are associated with insulin resistance in T2D (33,34). In addition, plasma CHI3L1 is associated with fasting plasma glucose and plasma IL-6 levels (35) and the development of coronary artery disease in patients with asymptomatic T2D (36).

Adiponectin is a colloidal protein secreted by adipose tissue, with a molecular weight of 29 kDa. Plasma adiponectin not only plays a role in obesity-related insulin resistance, but also stimulates the phosphorylation and activation of AMP kinase. Thus, adiponectin produces anti-inflammatory effects and protects endothelial cells (37). Results of a previous study revealed that CHI3L1 and adiponectin expression levels were elevated in patients with asymptomatic T1D in a European Mediterranean population, thus highlighting the potential of these proteins as markers of early inflammation in diabetic patients (38).

Collectively, these results reveal that CHI3L1 may be involved in insulin resistance, metabolic syndrome characterized by obesity and cardiovascular and metabolic disorders (39,40). Further research is required to fully elucidate the mechanisms underlying these associations and to explore the potential of CHI3L1 as a therapeutic target or biomarker for T1D/T2D and the associated complications.

Vascular inflammation is also a common cause of numerous cardiovascular diseases (41). Giant cell arteritis (GCA) is the most common systemic vasculitis in adults (42), and macrophages mediate the destruction and formation of blood vessels (43,44). Abdominal aortic aneurysm is a vascular inflammatory disease characterized by inflammatory cell infiltration, neovascularization, and the production of various proteases and cytokines. The formation of abdominal aortic aneurysm is associated with the degeneration of aortic elastic mediators, and vascular rupture is considered the most serious complication (45). Serum levels of CHI3L1 are elevated in patients with GCA and abdominal aortic aneurysm (43,44,46).

AS is also a vascular inflammatory disease. The lesion site is infiltrated by inflammatory cells, such as macrophages and T lymphocytes, and pro-inflammatory cytokines produced by these immune cells are a key cause of plaque rupture. In addition, results of previous studies reveal that regulating the gene expression of inflammatory factors affects the occurrence and development of AS (47,48). Results of previous studies also emphasize that AS progression is closely associated with CHI3L1 expression levels. Thus, CHI3L1 exhibits potential as a marker of coronary AS severity and plaque instability (49,50). Results of previous studies demonstrate that serum CHI3L1 expression levels are associated with arterial wall fibrosis and arterial stiffness (51–53). These findings support the notion that CHI3L1 upregulates abnormal lipid metabolism and vascular inflammation, which are risk factors for cardiovascular disease. Collectively, these results suggest that CHI3L1 may play a role in accelerating the development of cardiovascular disease through promoting the progression of these risk factors.

Previous research indicates that CHI3L1 serum levels may affect the risk of adverse cardiovascular outcomes and mortality (54). Results of a previous study using clinical data reveal that CHI3L1 levels are elevated in patients with cardiovascular disease and these elevated levels are often associated with disease progression (55). In addition, CHI3L1 is associated with mortality in individuals with cardiovascular disease (56). Serum CHI3L1 levels are increased in patients with essential hypertension, which is positively correlated with the incidence of hypertension in pre-hypertensive subjects (57). Monitoring CHI3L1 serum levels may aid in predicting the occurrence of cardiovascular events in patients with hypertension during long-term follow-up for 7.89±0.12 years (58). Results of previous studies also reveal that increased CHI3L1 serum levels in patients with aortic stenosis and peripheral artery disease are associated with a poor prognosis (59,60). Notably, CHI3L1 levels are elevated during the acute phase of ischemic stroke and are independently associated with recurrent stroke, complex vascular events and adverse functional outcomes (61). In patients with atrial fibrillation, CHI3L1 is highly expressed in epicardial tissue. Thus, serum CHI3L1 levels may be used to predict the recurrence of atrial fibrillation and may be associated with atrial fibrosis (62,63). Assessment of serum CHI3L1 may exhibit potential in identifying the risk of future cardiovascular events in additional diseases, such as essential thrombocythemia and polycythemia vera (64). In addition, CHI3L1 may affect the progression of coronary artery disease (CAD), affecting the stability of the fibrous cap of atherosclerotic plaques and the occurrence of complications. Thus, CHI3L1 may exhibit potential as significant indicator for the early diagnosis of CAD (65,66). Results of a previous study demonstrated a strong correlation between CHI3L1 levels and the progression of cardiovascular disease (67). These levels not only allow for the monitoring of disease progression, but also offer effective prediction of mortality caused by cardiovascular events, showcasing the potential of CHI3L1 as a valuable predictor of cardiovascular disease. Results of previous studies also highlight the effect of CHI3L1 on cardiovascular disease through the regulation of cardiovascular-related cells. In disease models of AS and pulmonary hypertension, CHI3L1 is closely associated with functions in specific cells, including macrophages and SMCs (25,55,68,69).

During the maturation of macrophages, the expression of CHI3L1 is upregulated due to the binding of nuclear transcription factor sp1 to the promoter of the CHI3L1 gene. Thus, CHI3L1 is considered a marker of macrophage maturation (70).

Results of a previous study indicated that individuals with Prader-Willi syndrome (PWS), a neurodevelopmental disorder, exhibit an increased risk of obesity and cardiovascular disease (71). The occurrence of PWS is associated with compromised macrophage suppression and increased ECM remodeling. Notably, patients with PWS exhibit elevated levels of MMP-9 and myeloperoxidase, along with reduced levels of macrophage inhibitory factor. In addition, patients with PWS exhibit elevated CHI3L1 expression levels, highlighting the potential association between CHI3L1 and macrophages (72). CHI3L1 expression has been detected in CD68+ macrophages and circulating monocytes in GCA, mediated by B cells (25). Cytokines produced by B cells promote the transformation of macrophages into pro-inflammatory phenotypes, and results of this study also demonstrated that CHI3L1, IL-6, IL-1β, TNF-α and MMP-9 expression levels were significantly increased (43). In GCA, CHI3L1 is mainly derived from CD206+MMP9+ macrophage subsets. As an upstream regulator of MMP-9+ macrophages, CHI3L1 binds to the IL-13Rα2, which is highly expressed in the vascular wall of GCA layers. Notably, IL-13Rα2 mediates tissue destruction and angiogenesis. In macrophages, CHI3L1 knockdown rescues the aforementioned effects (44). In M1 macrophages, IL-6 decreases the expression of microRNA (miR)-24-1, and upregulates the expression of CHI3L1 and inflammatory mediators, TNF-α and C-C motif chemokine ligand 2 (CCL2)MCP-1 during the progression of vascular inflammation. IL-6 mediates these effects through RelA (p65)/Nfkb1 (p50). In addition, upregulated CHI3L1 and its downstream inflammatory factor, CCL2, promote SMC migration through JNK and ERK phosphorylation pathways, stimulates the expression of vascular endothelial cell adhesion molecules, such as vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1 and P-selectin and enhances the adhesion function of monocytes (Fig. 2) (46).

The formation of plaque following accumulation of fat and/or fibrous material in the lining of the arteries is a major feature of AS, which involves the phagocytosis of plasma lipoproteins deposited in the lining of the arteries, with macrophages transforming them into foam cells (73). Serum CHI3L1 is significantly elevated in patients with symptomatic carotid AS (74). The initiation factor of AS, oxidized low-density lipoprotein (OX-LDL), also stimulates macrophages to secrete CHI3L1. These results suggest that CHI3L1 may play a role in the development of vascular diseases characterized by macrophage/monocyte accumulation and activation (Fig. 2) (25). Results of a previous study reveal that CHI3L1 gene knockout suppresses the expression of pro-inflammatory mediators, decreases plaque lipid and macrophage levels, and increases collagen and SMC content in ApoE (−/-) mice (75). In addition, CHI3L1 inhibits the activation of Caspase-9 and decreases the apoptosis of macrophages, resulting in plaque fiber cap damage (76).

MCP-1 is a chemokine secreted by adipose tissue that induces monocyte migration and macrophage infiltration and participates in the formation of atheromatous lipostreaks and the development of unstable plaques (77). Results of previous studies demonstrate that patients with obesity may exhibit increased CHI3L1 expression levels (78). However, CHI3L1 expression levels are reduced following weight loss in these patients. These results indicate that increased CHI3L1 expression levels induced the excessive accumulation of macrophages in obese patients, leading to a sub-inflammatory state and the occurrence of AS and other diseases (39,79,80).

Collectively, these results demonstrate that CHI3L1 is not only secreted by macrophages, but also acts on macrophages, facilitating macrophage activation and inflammation. This, in turn, leads to damage in cardiac vascular tissue. Thus, CHI3L1 may play a key role in the advancement of AS. Targeted elimination of CHI3L1 may delay the pathological progression of AS, highlighting its potential as a specific target in the treatment of AS, through the inhibition of inflammation.

Results of a previous study reveal that CHI3L1 stimulated the chemotaxis and migration of human umbilical cord vascular endothelial cells (81). Sun et al (68) demonstrate that CHI3L1 inhibits endothelial cell apoptosis during vascular remodeling in pulmonary hypertension, by co-binding to the transmembrane protein 219 (TMEM219) receptor and the corresponding IL-13Rα2 receptor. In addition, CHI3L1 upregulates oxygen regulatory protein through the peroxisome proliferator-activated receptor (PPAR)-δ-dependent pathway, reducing lipopolysaccharide (LPS)-induced phosphorylation of NFκB and inhibiting the expression of endothelial cell adhesion molecules, such as ICAM-1, VCAM-1 and E-selectin (Fig. 2) (82). Results of a previous study revealed that CHI3L1 and Lp-PLA2 RNAi in combination are superior to Lp-PLA1 or CHI3L1 RNAi alone in the treatment of AS (83). In a transgenic mouse model of amyloid precursor protein, miR-342-3p targeted the CHI3L13′-untranslated region (UTR) to inhibit CHI3L1 expression in endothelial cells, thereby inhibiting IL-6-induced monocyte-endothelial cell adhesion and platelet-derived growth factor (PDGF-BB)-induced cell migration and proliferation (Fig. 2) (69). Notably, CHI3L1 regulates endothelial cells to promote tumor angiogenesis. Small interfering RNA-mediated CHI3L1 knockdown inhibits tumor growth rate and blood vessel density in the glioblastoma U87 cell line. Anti-VEGF antibody exerts no effect on CHI3L1-mediated endothelial angiogenesis; thus confirming that CHI3L1 promotes tumor blood vessel formation as an angiogenic factor, independent of VEGF (84,85). In xenograft experiments, CHI3L1 expressed by tumor-derived mural cells (GSDCs) activates neural cadherin/β-catenin/smooth muscle α actin (SMA) and VE-cadherin/β between GSDC and endothelial cells. The catenin/actin pathway plays a role in mediating intercellular adhesion and permeability, enhancing the interaction between GSDCs and endothelial cells and stabilizing the vascular network. Results of a previous study reveal that CHI3L1 silencing in GSDCs leads to a significant reduction in tumor blood vessel density and stability, ultimately inhibiting tumor growth (86). In osteoblastoma cell lines; namely, MG-63 and U87, mouse monoclonal anti-CHI3L1 antibodies effectively inhibit the CHI3L1-induced activation of MAPK and ERK (1/2), thereby inhibiting the tube formation of microvascular endothelial cells (87). CHI3L1 also interacts with TGF-β to increase endothelial cell permeability and promote endothelial-to-mesenchymal transition (EMT). The treatment of bovine pulmonary artery endothelial cells with CHI3L1 in combination with TGF-β downregulates VE-cadherin in vascular endothelial cells and reduces the expression of α-SMA, a mesenchymal cell marker (Fig. 2) (68). Thus, CHI3L1 may play a role in promoting tumor angiogenesis and in mediating endothelial cell apoptosis and EMT. Targeting CHI3L1 may inhibit tumor growth, thus highlighting the potential of this protein in the development of novel treatment strategies.

Fibrosis is a tissue repair response that relies on fibroblast activation and is characterized by the excessive accumulation of ECM components, such as collagen and fibronectin (88). CHI3L1 stimulates fibroblast growth in a dose-dependent manner through MAPK and PI3K-AKT signaling pathways. Results of a previous study reveal that CHI3L1 mediates mitotic reactions, stimulates the proliferation of connective tissue cells and participates in fibrosis (89). During the wound healing process in diabetic foot ulcer, fibroblasts overexpressing CHI3L1 are enriched and M1-type macrophages are polarized (90). Notably, CHI3L1 is associated with atrial fibrosis in patients with atrial fibrillation (62). Results of a previous study reveal that CHI3L1 affects the degree of fibrosis in mouse cardiomyocytes by modulating the long non-coding (lnc)RNA TUG1/miR-1-495-3p/ETS proto-oncogene 1 (ETS1) axis. CHI3L1 increases the expression of lncRNA TUG1 and reduces the expression of miR-495-3p, thereby weakening the targeted binding of miR-495-3p to the 3′UTR sequence of the ETS1 gene. Thus, ETS1 gene expression levels are increased in mice, ultimately leading to increased levels of myocardial fibrosis (Fig. 2) (91). Collectively, these studies revealed that CHI3L1 may play a crucial role in the advancement of fibrosis in cardiovascular patients; thus highlighting its potential in the development of novel treatment options for fibrosis.

CHI3L1 participates in the morphological and phenotypic transformation of SMCs (92). During bronchial remodeling in patients with asthma, CHI3L1 stimulates IL-8 expression through PAR-2, AKT, ERK and P38-dependent mechanisms and promotes the proliferation and migration of bronchial SMCs (93,94). Although pulmonary artery SMCs do not express CHI3L1, CHI3L1 interacts with the G-protein-coupled receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), expressed by vascular SMCs. Thus, CHI3L1 promotes the proliferation of vascular SMCs and the formation of fibrosis during pulmonary hypertension vascular remodeling (68). TGF-β, a stimulator of hypoxia and fibrosis, also upregulates the expression of CRTH2, which exerts synergistic effects with CHI3L1 (68). Results of a previous study demonstrate that CHI3L1 and α-SMA co-localize in unstable plaques and CHI3L1 inhibits vascular SMC proliferation. In apo-/-mouse, CHI3L1 gene knockout results in a decrease in α-SMA+ cells localized in the plaque cap region and decreases plaque stability (95,96) (Fig. 2). In addition, in the presence of the atherosclerotic stimulant OX-LDL, large tumor suppressor kinase 2 (LATS2) expression levels are increased in human carotid SMCs. In addition, LATS2 knockdown in vitro inhibits the expression of the macrophage marker, advanced glycation end-product receptor 3 (LGALS3), and inflammatory cytokines, such as IL-6 and IL-1β. Results of a previous study highlights that CHI3L1 may reduce the expression of LATS2 and homologous domain-associated protein kinase 2 (96). These results reveal the role of CHI3L1 in the transition to a synthetic phenotype and in inhibiting SMC proliferation in atherosclerosis. Notably, the regulatory effect of CHI3L1 on SMCs varies depending on the disease; thus, further investigations are required to elucidate the specific underlying mechanisms.

Collectively, these results suggest that CHI3L1 may play a role as a crucial mediator in the development and progression of cardiovascular disease. Prolonged nicotine consumption exacerbates inflammatory responses through upregulation of CHI3L1, thereby heightening the risk and advancement of abdominal aortic aneurysm. Notably, this may be associated with reduced microRNA-24 expression (97). In male patients with end-stage renal disease, CHI3L1 expression is associated with vascular calcification, indicating the sex-specific role of CHI3L1 as a novel marker for cardiovascular disease that may affect the development of cardiovascular comorbidities (22). Through proteomics and Mendelian randomization, results of a previous study reveal that CHI3L1 acts as a circulating protein that is causally associated with the treatment of heart failure. Thus, CHI3L1 may exhibit potential in the treatment of heart failure (98).

CHI3L1 is not only associated with the development of cardiovascular disease, but also serves as a valuable indicator for monitoring the prognosis of patients. Notably, CHI3L1 may affect disease progression by modulating the functional status of cells associated with the cardiovascular system. As a novel predictor of cardiovascular disease, CHI3L1 exhibits potential as a target for disease management.

As signaling proteins, chemokines bind to corresponding receptors on the cell surface, to play key roles in angiogenesis and in the regulation of leukocyte adhesion and migration (99). Notably, CHI3L1 gene expression is negatively correlated with the expression of CCL2/MCP-1. Interference with the CHI3L1 gene inhibits the occurrence of inflammation in AS (83). In addition, CHI3L1 induces the secretion of IL-8 and CCL2 in macrophages, promoting the migration of macrophages and endothelial cells (100). In lung macrophages, CHI3L1 promotes CXCL2 production. Results of a previous study also demonstrate that CHI3L1 promotes the expression of LPS-treated macrophage angiogenesis factors, leading to further increases in angiogenesis (101).

As an inflammatory molecule, CHI3L1 is used in combination with VCAM-1 and ICAM-1 to evaluate the occurrence of vascular inflammation (102). Serum CHI3L1, VCAM-1 and ICAM-1 are significantly increased in vascular endothelial injury and vascular inflammation induced by high cholesterol (103). Results of a previous study reveal that CHI3L1 promotes a decline in endothelial barrier function by reducing the expression of VE-cadherin (68). During the formation of tumor blood vessels, CHI3L1 stimulates endothelial cells to upregulate the membrane receptor sydecan-1 protein to coordinate integrin αvβ3, triggering a signaling cascade of focal adhesion kinase and ERK-1/2; thus promoting angiogenesis (104). Proteoglycan also plays a key role in regulating cell adhesion and migration. Notably, CHI3L1 binds to proteoglycans, such as chitosaccharides and hyaluronic acid; thus playing a regulatory role in a variety of diseases (105).

ILs play a key role in inflammatory response and regulate the progression of AS (106). In high-cholesterol rats with vitamin D deficiency, IL-6 and CHI3L1 levels are simultaneously increased, promoting vascular inflammation (103). Results of a previous study reveal that CHI3L1 specifically binds to IL-13Rα2, increases the phosphorylation of ERK1/2 and JNK, promotes the recruitment of members of the activator protein-1 family in the nucleus, targets the MMP family and degrades the ECM (107). In lung tissue and airway remodeling, IL-13 upregulates the expression of CHI3L1 and plays a key role in the inflammatory response (108).

MMPs are a class of zinc-dependent endoproteases secreted by endothelial cells, vascular SMCs, fibroblasts, macrophages and neutrophils. MMP expression levels are associated with vascular remodeling and stiffening and plaque stability (109). In AS, MMP-7 regulates the function of macrophages, leading to the generation of atherosclerotic unstable plaques. MMP-2, MMP-9, MMP-13, MMP-35 and MMP-42 increase the risk of plaque rupture through degradation of arterial elastin and increasing vascular calcification, leading to further AS development (109,110). Results of a previous study demonstrated that both MMP-9 and CHI3L1 were independent risk factors for unstable plaque formation (111). Mechanical stress, including shear force, is involved in vascular remodeling through the regulation of MMPs. Results of a previous study reveal that vascular inflammatory factor MMP-8 expression levels are decreased in a model of AS, following CHI3L1 gene knockout (83).