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We explored the role of RIPK3 in cytokine storm syndrome (CSS)-induced acute kidney injury induced by lipopolysaccharide (LPS) in wild-type and\n                    <jats:italic>Ripk3-<\/jats:italic>\n                    deficient mice. For the in vitro experiments, we treated both primary tubular epithelial cells and bone marrow-derived cells from wild-type and\n                    <jats:italic>Ripk3<\/jats:italic>\n                    -deficient mice with LPS.\n                    <jats:italic>Ripk3<\/jats:italic>\n                    deficiency improved renal function and increased survival in CSS, a common condition observed in severe infections and other scenarios, and protection was associated with reduced inflammation. Mechanistically, the necroptosis pathway did not play a key role in kidney protection by Ripk3 deficiency, and the NLRP3 inflammasome was partially implicated. Olink plasma proteomics identified IL-6 as the most upregulated inflammatory protein in the kidney and circulation, and it was most responsive to\n                    <jats:italic>Ripk3<\/jats:italic>\n                    deficiency.\n                    <jats:italic>Ripk3<\/jats:italic>\n                    -deficient mice had suppressed kidney, liver, and lung\n                    <jats:italic>Il-6<\/jats:italic>\n                    expression as well as suppressed kidney activation of STAT3, a transcription factor downstream of IL-6. In bone marrow chimeric mice, RIPK3-expressing bone marrow-derived cells were required to drive IL-6 expression, and AKI and kidney\n                    <jats:italic>Il-6<\/jats:italic>\n                    expression correlated with loss of renal function. In this regard, in vitro experiments have shown that RIPK3 mediates\n                    <jats:italic>Il-6<\/jats:italic>\n                    expression in bone marrow cells but not in tubular cells. Additionally, targeting the IL-6 receptor improves kidney function and reduces kidney inflammation in CSS-AKI. Kidney transcriptomic data of human AKI associated with COVID-19 CSS were consistent with activation of the RIPK3-IL-6 axis. The RIPK3-IL-6 axis in bone marrow cells mediates systemic inflammation and kidney injury induced by a cytokine storm, independent of the necroptosis and inflammasome pathways. Specific targeting of bone marrow RIPK3 may limit kidney inflammation, without the potential adverse effects of systemic RIPK3 targeting.\n                  <\/jats:p>","DOI":"10.1038\/s41419-026-08686-1","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T05:36:24Z","timestamp":1776231384000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The RIPK3-IL-6 axis mediates kidney injury in cytokine storm syndrome"],"prefix":"10.1038","volume":"17","author":[{"given":"Juan","family":"Guerrero-Mauvecin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Martin-S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Villar-G\u00f3mez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Carrasco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0679-9023","authenticated-orcid":false,"given":"Blanca","family":"Chinchilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sol","family":"Carriazo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio M.","family":"Martinez-Moreno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Mi\u00f1o-Izquierdo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel J.","family":"G\u00f3mez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria D.","family":"Sanchez-Ni\u00f1o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9805-9523","authenticated-orcid":false,"given":"Alberto","family":"Ortiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0255-5689","authenticated-orcid":false,"given":"Ana B.","family":"Sanz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"8686_CR1","doi-asserted-by":"crossref","unstructured":"Carriazo S, Perez-Gomez MV, Cordido A, Garc\u00eda-Gonz\u00e1lez MA, Sanz AB, Ortiz A, et al. 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He had stock in Telara Farma. The rest of the authors have no conflicts of interest to declare.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"714"}}