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Showalter Research Trust Fund","doi-asserted-by":"publisher","award":["080657-00002B"],"award-info":[{"award-number":["080657-00002B"]}],"id":[{"id":"10.13039\/100007114","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Type 1 diabetes (T1D) is characterized by autoimmune destruction of pancreatic \u03b2-cells, insulin insufficiency, and hyperglycemia. Receptor interacting protein kinase 1 (RIPK1) is a multifunctional regulator of cell fate with kinase and scaffolding functions, and we previously identified RIPKs as regulators of \u03b2-cell cytotoxicity in vitro. Here we report that Ripk1 expression is increased in islets from aged non-obese diabetic (NOD) mice and \u03b2-cells from T1D donors, suggesting that RIPK1 may drive cytokine- and autoimmune-mediated \u03b2-cell demise in T1D. Using NIT-1 \u03b2-cells derived from NOD mice, we observed that TNF\u03b1\u2009+\u2009IFN\u03b3 increases RIPK1 phosphorylation, caspase 3\/7 activity, and cell death. In contrast, this cytotoxicity was blocked with small molecule RIPK1 inhibition or in Ripk1 gene-edited (Ripk1\u0394) \u03b2-cells. Small molecule caspase inhibition studies and co-labeling of caspase 3\/7 activation and cell death in single cells revealed protection from caspase-dependent and -independent forms of death in Ripk1\u0394 cells. RNAseq uncovered differential cell death-, immune-, and identity-related gene expression, and kinome profiling identified changes in MAPK, Eph, JAK, and other kinase activity associated with protection from cell death in RIPK1 deficient \u03b2-cells. Furthermore, in vitro co-culture assays and in vivo adoptive transfer experiments revealed that NIT-1 Ripk1\u0394 cells are protected from autoimmune destruction by splenocytes isolated from diabetic NOD mice. Collectively, our findings indicate that RIPK1 promotes \u03b2-cell demise in response to cytokine and autoimmune stress via actions on gene expression and kinase signaling. Therapeutics targeting RIPK1 may provide novel opportunities for the prevention or treatment of autoimmune diabetes.<\/jats:p>","DOI":"10.1038\/s41419-026-08471-0","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T05:24:50Z","timestamp":1770873890000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["RIPK1 regulates \u03b2-cell fate via actions on gene expression and kinase signaling in a mouse model of \u03b2-cell self-reactivity"],"prefix":"10.1038","volume":"17","author":[{"given":"Christopher J.","family":"Contreras","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noyonika","family":"Mukherjee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arianna","family":"Harris-Kawano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Egan G.","family":"Mather","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nansalmaa","family":"Amarsaikhan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Davis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine A.","family":"Berryhill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madeline","family":"Peyton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debjyoti","family":"Kundu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaitlyn A.","family":"Colglazier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Addison S.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renato C. 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