International Journal of Molecular Sciences · 3 authors, 1 centre
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This review summarizes the role of CHI3L1 (YKL-40) in macrophage polarization and disease progression. CHI3L1 is elevated in many inflammatory diseases, cancers, and neurodegenerative disorders, and it predominantly promotes M2-like macrophage polarization. Targeting CHI3L1 with inhibitors or antibodies shows therapeutic promise in preclinical models, particularly for cancer and Alzheimer's disease.
**Background:** Chitinase 3-like 1 (CHI3L1), also known as YKL-40 in humans, is a 40 kDa secreted protein belonging to the 18-glycoside hydrolase family. Although it lacks chitinase activity due to mutations in critical active residues, it retains high affinity for chitin and is highly conserved across species. CHI3L1 is expressed by macrophages, neutrophils, tumor cells, and vascular smooth muscle cells, and its levels are significantly elevated in inflammatory diseases, cancers, and degenerative diseases. It is recognized as a biomarker and potential therapeutic target. This review aims to summarize the roles of CHI3L1 in macrophage polarization and various diseases, including diabetes, atherosclerosis, liver diseases, neurological disorders, and cancers.
**Methods:** This is a narrative review that synthesizes findings from multiple studies on CHI3L1. The authors discuss the correlation between CHI3L1 and macrophage polarization, therapeutic approaches targeting CHI3L1, and its involvement in specific diseases. The review includes data from in vitro cell studies, in vivo animal models, and human tissue/serum analyses. Key signaling pathways (e.g., JNK, ERK, MAPK, PI3K, STAT3/6, NF-κB) and receptors (e.g., IL-13Rα2, CD44, Galectin-3) are highlighted.
**Key Results:** CHI3L1 is closely associated with macrophage polarization, predominantly promoting M2-like polarization in most diseases. In breast cancer, co-culturing 4T1 cells with RAW264.7 cells increased serum CHI3L1, LCN2, and MMP-9 levels, promoting tumor metastasis. Silencing CHI3L1 or treating with recombinant CHI3L1 reduced IFN-γ from M2 macrophages. In atherosclerosis, CHI3L1 promotes PPARδ expression and inhibits NF-κB phosphorylation, suppressing TNF-α and MCP-1 secretion. In liver fibrosis, serum CHI3L1 levels are significantly elevated, and combined with hyaluronic acid, they improve diagnostic accuracy. In Alzheimer's disease, cerebrospinal fluid CHI3L1 levels are 77% higher in patients than in controls. In colorectal cancer, CHI3L1 shows an AUC of 0.97, specificity of 91.7%, and sensitivity of 96% for diagnosis. Several inhibitors have been identified: K284-6111 prevents CHI3L1 binding to IL-13Rα2 and inhibits lung cancer metastasis; G721-0282 inhibits osteosarcoma proliferation and reduces neuroinflammation; and anti-CHI3L1 antibodies enhance CD8+ T-cell cytotoxicity and reduce tumor growth.
**Clinical Implications:** CHI3L1 is a promising biomarker for multiple diseases, including diabetes, atherosclerosis, liver fibrosis, Alzheimer's disease, and cancers such as breast, endometrial, and colorectal cancer. Its role in promoting M2 macrophage polarization suggests that targeting CHI3L1 could modulate the immune microenvironment. Inhibitors and antibodies against CHI3L1 have shown efficacy in preclinical models, improving disease outcomes and demonstrating good biological safety. However, most research is limited to animal models, and clinical translation requires further validation. The combination of CHI3L1 with other markers (e.g., hyaluronic acid for liver fibrosis) may enhance diagnostic accuracy. Additionally, CHI3L1's interaction with immune checkpoints like PD-L1 suggests potential for combination immunotherapy.