{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T11:24:54Z","timestamp":1787052294716,"version":"build-2736575974"},"reference-count":67,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"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>Hemolytic anemias comprise inherited and acquired disorders characterized by premature red blood cell destruction. Increasing evidence indicates that many forms of hemolysis are accompanied by sustained inflammatory and immune activation. Red blood cell breakdown releases damage-associated molecular patterns, including free heme and hemoglobin, which activate innate immune pathways, endothelial cells and coagulation cascades. Interleukin-6 (IL-6) is a central mediator linking hemolysis to systemic inflammation, iron restriction and autoimmunity. In this review, we use a heuristic dual-axis framework in which hemolysis-induced IL-6 promotes hepcidin-dependent iron sequestration and acute-phase responses, while also supporting Tfh and Th17 responses, impairing regulatory T-cell function and sustaining autoreactive or alloreactive B cells. The conceptual advance of this framework is not to propose IL-6 as a uniform pathogenic mechanism, but to position IL-6 differently across hemolytic disorders according to the dominant initiating biology and level of evidence. These pathways may aggravate anemia, thrombosis and organ injury. We summarize evidence for IL-6 involvement in autoimmune hemolytic anemia, Castleman disease-associated cytopenias, sickle cell disease, thalassemia, paroxysmal nocturnal hemoglobinuria, congenital red-cell membrane and enzyme defects, and hyperhemolysis syndrome. We also discuss therapeutic strategies targeting IL-6, IL-6 receptor, JAK\/STAT signaling and IL-6 trans-signaling. Current clinical evidence remains limited, but IL-6-directed therapy may be rational in selected refractory immune-mediated or macrophage-activation-associated hemolytic disorders. Future studies should prioritize mechanism-based biomarkers and prospective, biomarker-stratified trials.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1919619","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T10:27:10Z","timestamp":1787048830000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Interleukin-6 in hemolytic anemias: from inflammatory pathways to therapeutic targeting"],"prefix":"10.3389","volume":"17","author":[{"given":"Manjun","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of 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