{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T16:09:53Z","timestamp":1781712593972,"version":"3.54.5"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>This review provides a systematic and critical examination of the multifaceted roles of the CX3CL1\/CX3CR1 axis in liver diseases. We emphasize its context-dependent duality\u2014exhibiting both pro- and anti-inflammatory, pro- and anti-fibrotic, and pro- and anti-tumor functions across different etiologies. Moving beyond a binary good or bad\u201d paradigm, we propose a contextual signaling model that integrates cellular source, microenvironmental cues, and intersecting pathways to explain its divergent roles. We synthesize recent advances in its involvement in NAFLD\/NASH, viral hepatitis, autoimmune hepatitis, schistosomiasis, liver fibrosis and hepatocellular carcinoma. The review critically evaluates the axis\u2019s potential as a biomarker, discusses methodological advances and limitations in human studies, and analyzes therapeutic strategies with a focus on translational challenges. We conclude with a forward-looking perspective on precision medicine approaches targeting this axis.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1763348","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T06:47:18Z","timestamp":1770187638000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["CX3CL1\/CX3CR1 axis in liver disease: context-dependent roles and balance"],"prefix":"10.3389","volume":"17","author":[{"given":"Jing","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Guo","sequence":"additional","affiliation":[{"name":"National 111\u201d Center for Cellular Regulation and Molecular Pharmaceutics, School of Life and Health Sciences, Hubei University of Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"110873","DOI":"10.1016\/j.cellsig.2023.110873","article-title":"CX3CL1 represses autophagy via CX3CR1\/CaMKIIdelta\/HDAC4\/Rubicon axis and exacerbates chronic intermittent hypoxia induced Kupffer cell apoptosis","volume":"111","author":"Li","year":"2023","journal-title":"Cell Signal"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23318","article-title":"CX3CL1 (fractalkine): a signpost for biliary inflammation in primary biliary cirrhosis","volume":"51","author":"Shimoda","year":"2010","journal-title":"Hepatology"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2007.09.008","article-title":"The fractalkine receptor CX3CR1 is involved in liver fibrosis due to chronic hepatitis C infection","volume":"48","author":"Wasmuth","year":"2008","journal-title":"J Hepatol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2009.00787.x","article-title":"CX3CL1\/fractalkine shedding by human hepatic stellate cells: contribution to chronic inflammation in the liver","volume":"13","author":"Bourd-Boittin","year":"2009","journal-title":"J Cell Mol Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-013-2920-6","article-title":"Chemokine-chemokine receptor CCL2-CCR2 and CX3CL1-CX3CR1 axis may play a role in the aggravated inflammation in primary biliary cirrhosis","volume":"59","author":"Sasaki","year":"2014","journal-title":"Digest. 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