CHI3L1, commonly known as the chitin protein, is a glycoprotein (with a molecular weight of approximately 40 kDa) expressed by the CHI3L1 gene located on chromosome 1q31-q32.35. CHI3L1 belongs to the 18-glycosyl hydrolase family, and its polypeptide chain consists of 383 amino acids. It has been named YKL-40, and owing to the N-terminal three amino acids at the N-terminal end of the peptide chain are tyrosine (Y), lysine (K), and leucine (L). The 18-glycosyl hydrolase family mainly includes chitinases and chitinase-like proteins (CLPs). Chitinases are proteins with true chitin-degrading ability, while CHI3L1 belongs to the CLPs. Due to a mutation in the catalytic residue glutamate, CHI3L1 does not possess hydrolase activity; however, it still has a high affinity for chitosan, binds to a variety of receptors, and induces a wide range of cellular responses (22, 23). Currently identified CHI3L1 receptors include heparin, collagen, IL-13Rα2, transmembrane protein 219 (TMEM219), galectin-3, and cluster of differentiation 44 (CD44). CHI3L1 functions by binding to the receptors.

For example, CHI3L1binds to CD44 and activates the ERK and Akt pathways, as well as phosphorylates β-catenin, which promotes metastasis in gastric cancer (24). In addition, CHI3L1 modulates the glioma microenvironment by interacting with galectin-3, increasing tumor immunosuppression, and promoting macrophage M2 polarization, a process that is negatively regulated by galectin-3-binding proteins by competing with galectin-3 for binding to CHI3L1 (25).

CHI3L1 is a highly evolutionarily conserved secreted protein, first discovered in 1992 by Johansen et al. in the cell culture of the human osteosarcoma cell line, MG63 (26). Immunofluorescence staining of liver specimens from patients with NAFLD revealed that CHI3L1 in liver tissue was mainly derived from macrophages. Studies have shown that CHI3L1 is also derived from a variety of cells, including neutrophils, fibroblasts, vascular smooth muscle cells, chondrocytes, HSCs, and tumor cells (27–29).

CHI3L1 synthesis and secretion are regulated by a variety of factors. Many cytokines such as IL-1β, IL-13, IL-6, and IFN-γ stimulate CHI3L1 expression, which in turn can regulate the expression of cytokines such as IL-6, IL-8, IL-12, IL-18, IFN-γ, and tumor necrosis factor (30). Non-coding RNAs such as miR-125-3p, miR-342-3p, and linc00963 regulate CHI3L1 through signaling pathways and play a key role in regulating inflammation-driven liver fibrosis (31–33). Sarma et al. (32) reported that CHI3L1 expression is regulated through the miRNA-449a/NOTCH1 axis and that stabilized p65 interacts with CCAAT/EBPα in the CHI3L1 promoter region to upregulate CHI3L1 expression in hepatitis C. Furthermore, factors such as aging, ECM changes, stress, and drugs also modulate CHI3L1 expression (34).

CHI3L1 is closely related to cell proliferation, apoptosis, cell differentiation, and cell invasion and is involved in embryonic development, inflammation, tissue remodeling, angiogenesis, and tumor metastasis (Figure 1); however, studies targeting serum CHI3L1 levels are limited (35). Additionally, CHI3L1 is involved in innate immune system and ECM remodeling and is associated with chronic viral hepatitis, alcoholic hepatitis, NAFLD, and other chronic liver diseases, with a close association between the degree of liver fibrosis and ECM synthesis (14, 36–38).

Hepatitis B virus (HBV) infection is a major global public health issue. WHO estimates that of the 296 million people chronically infected with HBV globally, nearly 820,000 died due to HBV-related diseases in 2019. Furthermore, in approximately 15–40% of untreated patients, HBV infection will progress to cirrhosis or hepatocellular carcinoma (HCC). As the world’s most populous country, China has approximately 100 million HBsAg carriers (prevalence, 7.8%), and the annual number of deaths from HBV-related liver diseases is 162,000, accounting for approximately 29% of HBV-related deaths globally (54). China has made efforts to reduce the incidence of HBV infection over the past three decades (55), and aims to be a major contributor to the WHO’s goal of “eliminating viral hepatitis as a major public health threat by 2030.”

CHB is a dynamically progressive disease, and several clinical studies have shown that timely and effective antiviral therapy can slow or even reverse CHB-induced liver fibrosis (56, 57). The American Association for the Study of Liver Diseases and Asian Pacific Association for the Study of Liver Diseases guidelines recommend antiviral therapy for patients when the alanine transaminase (ALT) levels that are twice the upper limit of normal (ULN) levels (58, 59). However, in Chinese patients with CHB, ALT levels and the degree of fibrosis are not consistent, regardless of the HBe-Antigen (HBeAg) status and HBV DNA levels. Moreover, significant hepatic fibrosis has also been present in patients with CHB and an ALT level less than twice the ULN (21). Therefore, in the 2022 Expert Opinion on Expanding Antiviral Therapy for CHB, published by the Chinese Medical Association’s Section of Hepatology, it was suggested that antiviral therapy be initiated when a non-invasive diagnosis suggests significant inflammation or fibrosis in the liver (60).

Serum CHI3L1is associated with a high diagnostic value in CHB-related liver fibrosis. In HBeAg-negative patients with CHB, serum CHI3L1 has high diagnostic efficiency in the staging of liver fibrosis, with a sensitivity and specificity of 80.00 and 71.05%, respectively (11). In patients with CHB and an ALT less than twice the ULN, serum CHI3L1 levels are independently associated with advanced liver fibrosis and serve as a potential biomarker for liver fibrosis. The study also constructed a model based on CHI3L1, which significantly outperformed the existing scores in patients with CHB having normal and mildly elevated diagnostic ALT levels (FIB-4, APRI, Huu Model, and Forns’ index). This finding may guide clinicians in diagnostically identifying patients who may benefit from antiviral therapy (21).

Huang et al. (20) used univariate and multivariate logistic regression analyses to identify three independent predictors of advanced liver fibrosis in 337 patients with CHB (CHI3L1, AFP, and PLT indexes), and a new diagnostic model was established, namely, the CHI3L1/AFP/PLT (CAP) index. This index facilitated the diagnosis of advanced liver fibrosis with an AUROC significantly higher than that in the APRI and FIB-4, which is more suitable for patients with CHB. The diagnostic efficacy in advanced liver fibrosis is not affected by ALT level and HBeAg status, making it suitable for patients with CHB at different stages and helps in predicting the timing of antiviral therapy in these patients. A research team from Ningbo University examined the serum CHI3L1 expression in patients with CHB, liver cirrhosis, and HCC and investigated the expression characteristics of chronic liver diseases related to hepatitis B in different stages. The results of the investigation showed that the expression level of CHI3L1 progressively increased from CHB and liver cirrhosis to HCC, and the CHI3L1 expression offers clinical value in evaluating the different stages of chronic liver diseases and may be used as an indicator to monitor the disease evolution (10). However, other similar studies have suggested that CHI3L1 levels cannot significantly differentiate early liver fibrosis (meta-analysis of histologic data in viral hepatitis [METAVIR]F0, F1, and F2) (12).

CHI3L1 is a useful non-invasive marker for assessing liver fibrosis prior to treatment in patients with CHB and monitoring changes in liver fibrosis during treatment. Lin et al. (38) compared serum CHI3L1 levels, the hepatic tissue collagen proportional area (CPA), and LSM in 131 patients with CHB who received entecavir antiviral therapy for 78 weeks and found that serum CHI3L1 levels decreased from baseline after 78 weeks of treatment and were positively correlated with CPA and LSM.

In conclusion, the value of CHI3L1 expression in assessing significant liver fibrosis in patients with CHB is clearer and superior to currently known non-invasive diagnostic methods, and it serve as a reliable reference for antiviral therapy. However, as the diagnosis of early stage liver fibrosis is not highly accurate, a more appropriate non-invasive indicator for an individual or combined diagnosis remains to be identified.

Hepatitis C infection is a global epidemic trend, and people of different sexes, ages, and ethnicities are generally susceptible to HCV. According to the WHO, approximately 58 million people worldwide are currently infected with HCV, and approximately 290,000 deaths are attributed to HCV infection annually. In 2020, China had the largest number of HCV-infected individuals (approximately 9,487,000 people) (61). HCV infection is prone to chronicity, with approximately 55–85% of cases of acute hepatitis C developing into CHC. Cirrhosis and HCC are the main causes of death in patients with CHC (62). There is no effective vaccine to prevent HCV infection; however, as the treatment of hepatitis C enters a new era in terms of direct antiviral agents (DAAs), with an increasing number of patients achieving a sustained virologic response (SVR), post-treatment benefits and clinical outcomes are fast becoming the focus for future studies. The prognosis of patients after viral clearance is closely related to the degree of fibrosis (63), the early diagnosis of HCV-associated hepatic fibrosis, and staging; thus, timely interventions are crucial.

Little is known concerning the progression of hepatic fibrosis after HCV eradication; however, recent studies have suggested that serum CHI3L1 levels may be a non-invasive marker for monitoring fibrosis in patients with CHC. Treatment with DAAs significantly and sustainably improved hepatic fibrosis in patients with CHC, with serum CHI3L1 levels being significantly lower at the end of treatment compared baseline levels (64–66). In one study involving 105 patients with CHC treated with DAAs, CHI3L1 was identified as a sensitive marker for monitoring changes in fibrosis during treatment and in the weeks after having reached an SVR. Early identification of treatment success at the end of treatment using CHI3LI levels may facilitate a timely shift to alternative treatments (64). Similar international studies have been conducted. Researchers at Helwan University studied the risk of HCC susceptibility in Egyptian patients with hepatitis C after SVR through DAA treatment and found that the CHI3L1 gene (rs880633) could serve as a strong predictor and risk factor for patients to develop HCC post-SVR (67). While some studies have suggested that diagnosis using non-invasive indicators can be confounded by factors such as liver inflammation, a study from the First People’s Hospital of Peking University concludes the utility of treatment with DAAs to achieve a rapid and significant reversal of hepatic fibrosis in addition to relieving inflammation and highlights that this regression can be detected as early as the end of therapy (66).

In summary, serum CHI3L1 levels are associated with the severity of fibrosis in CHC and its progression over time, which is clinically important for monitoring the degree of hepatic fibrosis and thus predicting the clinical outcome in patients with an SVR after treatment with DAAs. However, the benefits of CHI3L1 in the diagnosis of mild and severe fibrosis remain unclear.

In recent years, there has been a renewed focus on hepatitis D virus (HDV) in several countries and regions, and comprehensive reports have shown that there are approximately 15–20 million cases of HDV infection worldwide, which is equivalent to approximately 5% of the chronically infected population with HBV (68). HDV is a defective RNA virus that requires the aid of HBV to complete its life cycle. Compared with HBV infection alone, overlapping HBV/HDV infections accelerate disease progression. It has been estimated that 70% of patients infected with HDV develop cirrhosis within 5–10 years and 60% succumb to disease within 10 years, in addition to a 28% increase in the risk of HCC in those infected with HBV/HDV (69, 70).

In the process of eliminating the viral hepatitis public health threat, it is important to emphasize and act in relation to chronic HBV, HCV, and HDV infection. With the application of nucleoside (acid) analogs and polyethylene glycol interferon-alpha, CHB can be effectively controlled, resulting in HBsAg-negativity and potential reversal of hepatic fibrosis, or even re-compensation after decompensation, can be achieved in some patients. Therefore, hepatitis D is emerging as a chronic viral hepatitis that cannot be neglected in the process of eliminating viral hepatitis-related public health hazards. At present, there are few studies on the use of CHI3L1 for the diagnosis of liver fibrosis due to HBV/HDV overlapping infections. One study in the United States (34) detected CHI3L1 gene expression in the liver tissues of 64 patients with liver cirrhosis of different etiologies using quantitative reverse transcription polymerase chain reaction testing: CHI3L1 expression was significantly higher in the livers of patients with liver cirrhosis of various etiologies than in controls, with the highest in cirrhosis due to HDV, followed by HCV, HBV, and alcoholic cirrhosis. Interestingly, CHI3L1 was significantly higher in HDV than in HBV cirrhosis, despite HDV dependence on HBV. In the study, all patients with HDV-induced liver cirrhosis tested positive for serum HDV RNA and anti-HDV (IgG), with 82% of patients positive for anti-HDV (IgM). In addition, patients with HDV liver cirrhosis had the lowest platelet counts, consistent with typical splenomegaly, and the highest activity grading (p < 0.001) compared with alcohol-related cirrhosis and hepatitis C- and B-related diseases, reconfirming that hepatitis D is the most severe form of chronic viral hepatitis. In conclusion, chronic HDV infection is currently underappreciated and understudied in China, and the important role of CHI3L1 in chronic HDV progression and diagnosis needs to be further explored.

Currently, NAFLD is the most common chronic liver disease worldwide, with a prevalence rate of up to 25%. It is one of the leading causes of liver disease-related mortality (71). Characterized as excessive accumulation of liver fat, NAFLD is due to hepatic steatosis without excessive alcohol consumption and is a type of metabolic stress liver injury closely related to insulin resistance and genetic susceptibility, which mainly includes NASH, cirrhosis, and HCC. Approximately 20% of patients with NAFLD can progress to more severe NASH (72, 73), a severe type of NAFLD characterized pathologically by inflammation, hepatocellular injury, lipid degeneration, and fibrosis. With type 2 diabetes and obesity, NASH is increasingly becoming a public health concern, and, without clinical intervention, it can progress to severe liver diseases such as liver failure, cirrhosis, and HCC, potentially necessitating liver transplantation (72). Among various liver histologic indices, the liver fibrosis stage is an independent predictor of long-term prognosis in patients with NAFLD. Therefore, early identification of patients with NASH and significant fibrosis is crucial.

Integration of liver transcriptome datasets using the robust rank aggregation method to construct transcriptomic profiles of NASH progression and fibrosis severity in patients with NAFLD revealed that the CHI3L1 gene was located in the top 10 upregulated genes in patients with NASH (74). One study suggests that CHI3L1 may be a potential marker for predicting significant fibrosis in patients with NAFLD (75). Kumagai et al. (14) measured serum CHI3L1 levels in 111 patients with NAFLD and 23 patients with HCC combined with NAFLD and found that serum CHI3L1 levels in patients with NAFLD increased with the progression of hepatic fibrosis. Additionally, CHI3L1 was significantly correlated with severe fibrosis (F3–4), and patients with HCC combined with NAFLD had significantly higher serum CHI3L1 levels than patients with NAFLD and non-HCC.

Harrison et al. (19) developed and externally validated a new blood-based non-invasive diagnostic model, namely, the NIS4 score, consisting of the following four metrics: miR-34a-5p, α-2 macroglobulin, CHI3L1, and glycated hemoglobin, specifically designed to identify patients with metabolic risk factors (type 2 diabetes mellitus, obesity, dyslipidemia, and hypertension) in patients with high-risk NASH (including those with an NAFLD activity score ≥ 4 and fibrosis stage ≥2). This model offered improved NIS4 diagnostic performance and was not affected by age, sex, body mass index, or aminotransferase concentration. The study concluded that although the diagnostic efficacy of CHI3L1 alone was not significant, the NIS4 for high-risk NASH outperformed other blood-based diagnostic scores such as the FIB-4, the NAFLD fibrosis score(NFS), and APRI (NIS4, AUC = 0.80; CHI3L1, AUC = 0.69; APRI, AUC = 0.74; FIB-4, AUC = 0.70; NFS AUC = 0.66). The data also showed that while FIB-4 and NFS showed high specificity, their low sensitivities could lead to misleading diagnostic results for NASH, especially for the adjudication of high-risk NASH cases. In contrast, the sensitivity and specificity of NIS4 were optimally balanced. NFS mainly targets NAFLD-associated liver fibrosis; however, it is not a suitable screening indicator because it leads to overdiagnosis and high percentage of false negatives (76). The NIS4 model was further optimized in 2023 as the NIS2 + ™ (including miR-34a-5p and YKL-40), providing a more effective non-invasive method in which to rule out high-risk NASH for patients at risk (77).

Hepatic insulin resistance is known to have an important role in the development of NASH; however, the exact mechanism of action remains unclear. Zhang et al. (78) suggested that CHI3L1 gene upregulation may be an important factor in the generation of the NAFLD/NASH phenotype. The researchers constructed a CHI3L1 knockout mouse model and observed improved insulin signaling in the CHI3L1 knockout mice compared with C57BL/6 wild-type (WT) mice fed the same diet, suggesting that decreasing the expression of CHI3L1 in the liver or inhibiting its function could ameliorate insulin resistance in the liver. To further confirm this finding, three anti-CHI3L1 monoclonal antibodies (FRG, CH568, and CHXI3B6) were used in the study. All three anti-CHI3L1 monoclonal antibody proteins inhibited their in vivo functions of CHI3L1 to varying degrees and significantly improved insulin resistance in the liver after 16 weeks of anti-CHI3L1 monoclonal antibody treatment. Additionally, although the CHI3L1 protein was expressed at different levels in the hepatocytes of patients with NAFLD and NASH, the positive cells of both were mainly localized in the hepatoportal vasculature, and immunohistochemical staining revealed abundantly expressed CHI3L1 in infiltrating inflammatory cells and hepatocytes. Overall, CHI3L1 is important for the diagnosis of advanced NAFLD-associated hepatic fibrosis and increased CHI3L1 expression directly correlates with hepatic fibrosis progression. CHI3L1 is expected to be a therapeutic target against monoclonal antibodies, but its role in the mechanism of hepatic fibrogenesis needs to be further investigated. Future studies are required to confirm the role of CHI3L1 in hepatic fibrosis (that is, determine whether CHI3L1 is a co-existing hepatic fibrosis factor or whether it promotes the formation of hepatic fibrosis).

In addition to viral hepatitis and NAFLD, excessive alcohol consumption and autoimmune liver disease can lead to serious negative outcomes. Among the different types of fatty liver diseases, the incidence of alcohol-related liver disease(ALD) related cirrhosis and HCC is the highest (79). However, the main cause of cirrhosis in China at this stage is still viral hepatitis. Although viral hepatitis is currently the primary cause of cirrhosis in China, the proportion of alcoholic cirrhosis has seen an increase in recent years. The epidemiologic study in China is still in the primary stage. The risk of HCC in autoimmune hepatitis is lower than that of other chronic liver diseases. A long-term follow-up study based on 1,428 patients with autoimmune hepatitis (AIH) found that only 1.7% of patients developed HCC with cirrhosis, only mildly increased the risk of HCC (80). Clinical and basic research on autoimmune liver disease in China has just begun, and there is a lack of relevant epidemiologic information, resulting in serious clinical underdiagnosis and mistreatment. In contrast, the evaluation of CHI3L1 in ALD as well as AIH-associated hepatic fibrosis has been reported less frequently, underscoring the need for further exploration of the important role of CHI3L1 in their progression and diagnosis.