{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:50:10Z","timestamp":1790621410027,"version":"4.1.0"},"reference-count":64,"publisher":"American Society of Hematology","issue":"9","license":[{"start":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T00:00:00Z","timestamp":1668038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,3,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Intestinal epithelial cells (IECs) are implicated in the propagation of T-cell\u2013mediated inflammatory diseases, including graft-versus-host disease (GVHD), but the underlying mechanism remains poorly defined. Here, we report that IECs require receptor-interacting protein kinase-3 (RIPK3) to drive both gastrointestinal (GI) tract and systemic GVHD after allogeneic hematopoietic stem cell transplantation. Selectively inhibiting RIPK3 in IECs markedly reduces GVHD in murine intestine and liver. IEC RIPK3 cooperates with RIPK1 to trigger mixed lineage kinase domain-like protein-independent production of T-cell\u2013recruiting chemokines and major histocompatibility complex (MHC) class II molecules, which amplify and sustain alloreactive T-cell responses. Alloreactive T-cell\u2013produced interferon gamma enhances this RIPK1\/RIPK3 action in IECs through a JAK\/STAT1-dependent mechanism, creating a feed-forward inflammatory cascade. RIPK1\/RIPK3 forms a complex with JAK1 to promote STAT1 activation in IECs. The RIPK1\/RIPK3-mediated inflammatory cascade of alloreactive T-cell responses results in intestinal tissue damage, converting the local inflammation into a systemic syndrome. Human patients with severe GVHD showed highly activated RIPK1 in the colon epithelium. Finally, we discover a selective and potent RIPK1 inhibitor (Zharp1-211) that significantly reduces JAK\/STAT1-mediated expression of chemokines and MHC class II molecules in IECs, restores intestinal homeostasis, and arrests GVHD without compromising the graft-versus-leukemia (GVL) effect. Thus, targeting RIPK1\/RIPK3 in IECs represents an effective nonimmunosuppressive strategy for GVHD treatment and potentially for other diseases involving GI tract inflammation.<\/jats:p>","DOI":"10.1182\/blood.2022017262","type":"journal-article","created":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T16:56:04Z","timestamp":1668099364000},"page":"1070-1086","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":46,"title":["A novel RIPK1 inhibitor reduces GVHD in mice via a nonimmunosuppressive mechanism that restores intestinal homeostasis"],"prefix":"10.1182","volume":"141","author":[{"given":"Xiaoliang","family":"Yu","sequence":"first","affiliation":[{"name":"1Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China"},{"name":"2Suzhou Institute of Systems Medicine, Suzhou, China"},{"name":"3Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haikuo","family":"Ma","sequence":"additional","affiliation":[{"name":"4Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2952-146X","authenticated-orcid":false,"given":"Bohan","family":"Li","sequence":"additional","affiliation":[{"name":"5Department of Hematology, Jiangsu Pediatric Center of Hematology & Oncology, and The Children\u2019s Hospital of Soochow University, Suzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Ji","sequence":"additional","affiliation":[{"name":"1Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union 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