{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nXCL1 (also known as lymphotactin) is a unique “metamorphic” chemokine that dynamically interconverts between two distinct native conformations. In one state, XCL1 adopts the canonical chemokine fold that activates its specific G protein–coupled receptor, XCR1, thereby mediating directed leukocyte chemotaxis. In its alternative, dimeric all‐β structure, XCL1 displays high‐affinity binding to glycosaminoglycans and underpins potent antimicrobial and anti–HIV-1 activities via direct interactions with viral envelope proteins. Detailed structural studies have mapped critical residues within the amino terminus and large positively charged surface patches that differentially contribute to XCR1 activation versus glycosaminoglycan engagement. Moreover, biophysical and computational analyses have illuminated the thermodynamic and evolutionary underpinnings of XCL1’s fold-switching behavior, establishing its dual structural states as central to its diverse molecular functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its intrinsic structural dynamics, XCL1 plays multifaceted roles in immune regulation and inflammation. It is predominantly produced by activated CD8⁺ T cells and natural killer cells, and its expression is tightly linked to the functional status of these lymphocyte subsets. XCL1 mediates tissue-specific recruitment of dendritic cells expressing XCR1, thus fine-tuning both innate and adaptive immune responses. Pathologically, aberrant or dysregulated XCL1 expression has been associated with inflammatory and autoimmune conditions such as IgA nephropathy, systemic sclerosis, Wegener’s granulomatosis, multiple sclerosis, and HTLV-1–associated myelopathy. In these contexts, XCL1 appears to modulate leukocyte trafficking and may promote the infiltration of autoreactive T cells into affected tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, XCL1 has emerging roles as a critical biomarker and mediator in oncogenesis and tissue homeostasis. In cancer, for instance, altered XCL1 expression is linked to malignant transformation and progression in certain carcinomas, where it can influence tumor microenvironment dynamics by recruiting dendritic cells and modulating PD-L1 expression. In breast cancer, genetic variants that upregulate XCL1 correlate with improved survival, while paracrine actions of XCL1 have been implicated in promoting epithelial-to-mesenchymal transition and cell migration. In other settings, circulating XCL1 levels are modulated by physical exercise, a change that may contribute to enhanced adult hippocampal neurogenesis. Additionally, under conditions of cellular stress such as exposure to environmental carcinogens, XCL1 functions as a direct p53 target gene to mediate apoptosis in lymphoblasts, further underscoring its diverse impact on cell fate decisions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "E Sonay Kuloğlu, Darrell R McCaslin, John L Markley, et al. 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