The study, published in Biotechnology for Biofuels and Bioproducts by Alex Windels, Shari Dhaene, and Tom Desmet of the Centre for Synthetic Biology, began not with a new organism but with a new way of looking at old data. The team systematically re-examined archaeal enzymes belonging to glycoside hydrolase family 18 (GH18), a well-characterized family of chitin-degrading enzymes, using a domain annotation pipeline called CANDy. Rather than searching for entirely novel sequences, they searched for unusual domain arrangements within known families — an underexplored strategy that treats enzyme architecture itself as a clue to hidden functionality.

That strategy paid off when CANDy flagged a chitinase from T. chitonophagus that did not look like a typical GH18 enzyme at all. Instead of a single catalytic domain, TcChi carries two: a GH12 domain, normally associated with cellulose degradation, fused to a GH18 chitinase domain, along with two carbohydrate-binding modules that likely help the enzyme anchor itself to insoluble polysaccharide surfaces. The researchers hypothesized that this composite assembly might have evolved a broader functional range than either domain alone — a hypothesis their biochemical assays confirmed in striking fashion.

To test what each part of the protein could actually do, the team constructed truncated versions of TcChi containing the individual catalytic domains and measured their activity against a panel of polysaccharide substrates. The GH18 domain, the “chitinase” half of the protein, did what its family assignment predicted and hydrolyzed chitin, the tough structural polymer found in crustacean shells and fungal cell walls. But it also degraded chitosan, a deacetylated derivative of chitin, and — most remarkably — β-1,3-glucan, a glucose polymer that forms structural elements in fungi and algae. This β-1,3-glucanase activity corresponds to enzyme commission number EC 3.2.1.58, and the study marks the first time this activity has ever been reported in a GH18 chitinase.

The GH12 domain proved equally surprising. As expected from its family membership, it showed strong cellulase activity, breaking down cellulose, the dominant structural polymer in plant biomass. But it also displayed chitosanase activity (EC 3.2.1.132), a function not previously associated with GH12 enzymes, extending the known catalytic range of this family in the opposite direction. In other words, each half of TcChi exceeds the functional repertoire of its assigned family, and together they cover a polysaccharide spectrum spanning marine, fungal, and plant biomass in one protein scaffold.

A key practical property of both domains is their thermostability. T. chitonophagus is a hyperthermophile, an organism adapted to life at very high temperatures, and its enzymes inherit this resilience. Thermostable biocatalysts are prized in industrial biotechnology because they tolerate the elevated temperatures that improve substrate solubility, accelerate reaction rates, and reduce contamination risk in large-scale bioreactors. TcChi’s robustness at high temperatures, consistent with its origin, makes it an attractive candidate for harsh industrial settings where mesophilic enzymes would denature.

The implications for biomass valorization are considerable. Lignocellulosic plant matter, crustacean shell waste, and fungal cell walls each represent enormous, underused streams of renewable carbon. Chitin, in particular, is one of the most abundant biopolymers on Earth thanks to the seafood processing industry, yet its crystalline structure resists degradation. A single enzyme capable of attacking chitin, chitosan, cellulose, and β-1,3-glucan simultaneously could simplify “consolidated biomass deconstruction” — the long-sought goal of converting mixed feedstocks into fermentable sugars in one pot — by replacing multiple enzyme preparations with one multifunctional catalyst. That reduces cost, complexity, and the need to match specific enzyme cocktails to specific substrates.

Beyond its immediate application potential, the study makes a broader methodological argument. Glycoside hydrolases — often called CAZymes, for carbohydrate-active enzymes — are among the most extensively cataloged enzyme classes in biology, organized into families based on sequence, structure, and catalytic mechanism. The conventional assumption is that family membership largely predicts function. TcChi demonstrates that this assumption can blind researchers to real diversity: two domains residing in “well-characterized” families each turn out to do something their families were not known to do. The Ghent team’s domain-centric approach — using computational annotation to systematically hunt for unusual multidomain assemblies across thousands of characterized sequences — offers a scalable template for finding similar surprises.

There is also an evolutionary dimension worth noting. T. chitonophagus encodes dedicated standalone cellulases and chitinases in addition to the fused TcChi, raising the question of why it maintains a multifunctional hybrid at all. The authors suggest the multidomain architecture may have evolved under selective pressure to exploit mixed polysaccharide substrates efficiently, with the carbohydrate-binding modules helping the enzyme process heterogeneous material. The fusion of a chitinase domain with a cellulase domain in one scaffold is an elegant natural solution to the same engineering problem that biotechnologists pursue when they artificially fuse enzyme domains — but here it arrived ready-made, honed by evolution in a hot marine environment.

For the bioeconomy, enzymes like TcChi arrive at a moment of growing urgency. Converting waste biomass — shrimp shells, fungal mycelium, agricultural residues — into sugars, platform chemicals, and biofuels depends on affordable, stable, and versatile biocatalysts. Multifunctional, thermostable enzymes that degrade several recalcitrant polysaccharides from a single protein could meaningfully lower the enzymatic cost of these processes. The research was supported by the FWO Bioeconomy Research Project “MyCOS” and funding from the European Union’s NextGenerationEU program, reflecting the strategic priority European funders place on biobased valorization of renewable feedstocks.

The work is unlikely to remain an isolated case. As domain annotation tools like CANDy are applied across the rapidly expanding databases of archaeal and bacterial genomes, other multidomain CAZymes with unexpected substrate ranges are likely to surface. TcChi is a reminder that even the most familiar enzyme families still hold unexplored chemistry — and that sometimes the fastest route to a novel biocatalyst is not discovering a new organism, but reading the domain architecture of a known one more carefully.

Liver disease remains a formidable global health burden. Conditions such as hepatitis-induced fibrosis, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and hepatocellular carcinoma (HCC) collectively account for extensive morbidity and mortality worldwide. Traditional diagnostic modalities, notably liver biopsy, while considered the gold standard, suffer from significant drawbacks including invasiveness, sampling error, and patient discomfort. The emergent paradigm shift toward serum biomarkers opens avenues for less invasive, repeatable, and dynamic assessment of liver pathology. CHI3L1’s ability to reflect the state of hepatic fibrosis and inflammation has thus garnered intense research interest.

Elevated circulating levels of CHI3L1 have been correlated robustly with the severity of hepatic fibrosis, especially in chronic viral hepatitis contexts such as chronic hepatitis B (CHB) and chronic hepatitis C (CHC). Comparative analyses have revealed that CHI3L1 surpasses conventional serum markers like hyaluronic acid (HA) and the Fibrosis-4 (FIB-4) index in diagnostic accuracy for fibrosis staging. These findings underscore CHI3L1 as a promising candidate for non-invasive fibrosis evaluation. Additionally, this marker’s dynamic range permits nuanced tracking of fibrosis progression or regression over time, augmenting its clinical utility.

Beyond static diagnosis, CHI3L1 exhibits pronounced potential as a biomarker to monitor therapeutic efficacy, notably antiviral regimens. The protein’s serum concentrations correspond proportionally with fibrosis stage; thus, changes in CHI3L1 levels provide real-time insights into the liver’s response to treatment. This realignment of biomarker use—from purely diagnostic to active disease monitoring—heralds a transformative approach to managing chronic liver conditions, wherein patient-tailored interventions can be fine-tuned based on biomolecular feedback.

Further expanding its clinical relevance, CHI3L1 demonstrates capacity to discriminate between benign hepatic steatosis and non-alcoholic steatohepatitis (NASH). This distinction is pivotal, as NASH is a progressive and potentially oncogenic condition characterized by hepatocellular injury, inflammation, and fibrosis, whereas simple steatosis remains relatively benign. Accurate differentiation via CHI3L1 levels could facilitate early intervention strategies, forestalling progression to cirrhosis or hepatocellular carcinoma.

Strategically combining CHI3L1 with other serum markers amplifies diagnostic precision. Incorporation with alpha-fetoprotein (AFP), platelet counts, and other fibrosis indices have proven especially efficacious in detecting significant and advanced fibrosis stages. This multifaceted biomarker matrix strengthens clinical decision-making frameworks, facilitating early identification of high-risk patients and enabling timely therapeutic escalation.

Hepatocellular carcinoma, a lethal sequela of chronic liver disease, is another domain where CHI3L1 has shown remarkable prognostic significance. Elevated CHI3L1 levels have been linked with poorer survival outcomes, particularly following curative hepatic resections. When considered alongside AFP, CHI3L1 enhances early detection accuracy for HCC, offering clinicians a dual-marker system that surpasses the sensitivity and specificity of either marker alone. This synergistic diagnostic approach promises improved surveillance and risk stratification in at-risk populations.

On a mechanistic level, CHI3L1 functions as a pivotal regulator of fibrogenesis and inflammatory pathways. By modulating macrophage activity, hepatic stellate cell proliferation, and extracellular matrix deposition, CHI3L1 actively shapes the hepatic microenvironment favoring fibrosis and tumorigenesis. Targeting these molecular interactions may unlock new therapeutic strategies aimed at halting or reversing liver disease progression. As such, CHI3L1 transcends its utility as a biomarker, emerging as a viable target for pharmacological intervention.

Current research delves deeper into the molecular cascades influenced by CHI3L1. Detailed elucidation of its receptor interactions, downstream signaling pathways such as MAPK and PI3K/AKT, and crosstalk with inflammatory cytokines will refine our understanding of liver pathobiology. This knowledge will be instrumental in designing inhibitors or modulators of CHI3L1 activity, potentially yielding novel antifibrotic and anticancer drugs tailored to liver disease patients.

Clinically, integrating CHI3L1 assessments into routine workflows could revolutionize patient management paradigms. Non-invasive CHI3L1 measurements would enable serial monitoring of disease course, early detection of fibrosis exacerbation, and timely adjustment of therapeutic regimens. This biomarker-driven, precision medicine approach promises to enhance patient outcomes, reduce reliance on invasive biopsies, and optimize resource utilization in hepatology practice.

Moreover, the prognostic implications of CHI3L1 extend beyond liver diseases. Emerging evidence from oncology and immunology suggests that its expression impacts tumor microenvironments and systemic inflammatory states, potentially linking CHI3L1 to broader pathological contexts. This cross-disciplinary relevance underscores the translational potential of CHI3L1-centered research and may stimulate novel investigations into diverse chronic diseases involving fibrosis and inflammation.

In summary, the identification and characterization of CHI3L1 as a multifunctional biomarker and regulator in liver diseases mark a significant advance in hepatology. Its diagnostic, prognostic, and therapeutic implications portend a new chapter in managing chronic liver conditions and HCC. Ongoing and future studies will further clarify its mechanistic roles, refine its clinical applications, and possibly introduce targeted therapies that leverage its biological functions. The integration of CHI3L1 into personalized medicine algorithms exemplifies the cutting edge of translational biomedical research, with tangible benefits for millions affected by liver ailments globally.

Subject of Research: Chitinase-3-like protein 1 (CHI3L1) as a biomarker and therapeutic target in liver diseases

Article Title: Role of chitinase-3-like protein 1 in liver diseases: A comprehensive review

News Publication Date: 2025

References:
Chao Tian, Shizhou Deng, Ming Yang, Baochen Bai, Lai Wei, Role of chitinase-3-like protein 1 in liver diseases: A comprehensive review, Genes & Diseases, Volume 12, Issue 6, 2025, 101653

Image Credits: Genes & Diseases

Keywords: Cancer genetics, Liver fibrosis, Biomarkers, Hepatocellular carcinoma, Non-alcoholic steatohepatitis, Chronic hepatitis B, Chronic hepatitis C, Antiviral therapy monitoring, Fibrosis progression, Inflammation, Molecular targets