{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Complement C1r‐like protein (C1RL) is emerging as a multifunctional component of the complement system with dual roles in proteolytic processing and immunomodulation. Early studies demonstrated that C1RL exhibits serine protease activity that mediates the cleavage of secretory protein precursors such as pro‐haptoglobin in the endoplasmic reticulum, thereby contributing to the maturation of circulating proteins critical for innate immunity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In several cancer studies, C1RL is found to be deregulated; its expression is notably elevated in glioblastoma, particularly in mesenchymal or IDH1–wild type subgroups, where high C1RL expression associates with enhanced immune responses marked by M2 macrophage infiltration and poorer clinical outcomes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In hepatocellular carcinoma, C1RL emerged among a panel of hub genes whose expression correlates with malignant progression and adverse prognosis, implying a role in tumor development and/or modulation of the tumor microenvironment."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond oncology, alterations in C1RL levels have been implicated in diverse inflammatory and immune-mediated conditions. In metabolic syndrome, for example, differential expression of C1RL was observed between caloric‐restriction regimes and regimens supplemented with protein, linking C1RL to inflammatory and complement‐driven responses that correlate with alterations in key blood lipids and glucose levels."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Similarly, in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and in COVID-19 patient plasma, C1RL is significantly up-regulated as part of broader complement activation and immune response profiles, suggesting its involvement in modulating disease severity and immunopathology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Genetic studies have also pointed to the clinical relevance of C1RL. Polymorphism analyses indicate that variants in complement-related genes—including C1RL—may influence susceptibility to immune-mediated disorders such as systemic lupus erythematosus and non-Hodgkin lymphoma, while plasma levels of C1RL are additionally linked with functional outcomes in individuals at high risk for psychosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, the body of work on C1RL reveals that it not only participates in the proteolytic activation of key serum proteins but also plays a significant role in modulating complement activity and immune responses across tumorigenic, metabolic, and inflammatory contexts. The altered expression and genetic variability of C1RL in these diverse pathologies underscore its potential as both a biomarker and a therapeutic target in conditions marked by aberrant complement and immune functionality.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Krzysztof B Wicher, Erik Fries "}, {"type": "b", "children": [{"type": "t", "text": "Prohaptoglobin is proteolytically cleaved in the endoplasmic reticulum by the complement C1r-like protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0405692101"}], "href": "https://doi.org/10.1073/pnas.0405692101"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15385675"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15385675"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Junyou Wang, Luqing Tong, Gaojun Lin, et al. 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