ArticleBlood2023
A novel RIPK1 inhibitor reduces GVHD in mice via a nonimmunosuppressive mechanism that restores intestinal homeostasis.
Article in Blood, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 36 citations in OpenAlex.
- A phase I, randomized, ascending-dose study to assess safety, pharmacokinetics, and activity of GDC-8264, a RIP1 inhibitor, in healthy volunteers.Clinical and translational science · 2023Trial
- Necroptosis and the RIPK1-RIPK3-MLKL pathway in chronic kidney disease: mechanisms, crosstalk, and therapeutic opportunities.Renal failure · 2026Review
- HERC4-mediated ubiquitination licenses RIPK1 to initiate TNF-induced cell death.Nature structural & molecular biology · 2026Article
- RIPK3 sequentially recruits MLKL and RIPK1 to induce PANoptosis and chemokine production.Cell death and differentiation · 2026Article
- A viable kinase-inactive RIPK3 D143N mouse model reveals its scaffold function in driving TNF-induced inflammatory disorder.Cell death discovery · 2026Article
- Receptor-Interacting Protein Kinase 1 (RIPK1): A Potential Therapeutic Target in Ischemic Stroke.Molecular neurobiology · 2026Review
- A glucose kinase-independent HK2 activity prevents TNF-induced cell death by phosphorylating RIPK1.Nature communications · 2025Article
- Necroptotic cell death consequences and disease relevance.Nature immunology · 2025Review
- Insights from human NF-κB knockouts.EMBO reports · 2025Review
- AIM2 activation mediated by RIPK1/3-dependent mitochondrial DNA release drives AβCell communication and signaling : CCS · 2025Article
- PARP12-mediated mono-ADP-ribosylation as a checkpoint for necroptosis and apoptosis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Mendelian randomization analysis of blood metabolites and immune cell mediators in relation to GVHD and relapse.BMC medicine · 2025Article
- Cysteine‑ and glycine‑rich protein 2: A vital regulator that inhibits necroptosis glioma cell by activating the JAK‑STAT1 pathways.Oncology reports · 2025Article
- RIPK1 in necroptosis and recent progress in related pharmaceutics.Frontiers in immunology · 2025Review
- Targeting necroptosis: a promising avenue for respiratory disease treatment.Cell communication and signaling : CCS · 2024Review
- Article
- Structure-based development of potent and selective type-II kinase inhibitors of RIPK1.Acta pharmaceutica Sinica. B · 2024Article
- Mechanisms of PANoptosis and relevant small-molecule compounds for fighting diseases.Cell death & disease · 2023Review
- Inhibition of RIP1 improves immune reconstitution and reduces GVHD mortality while preserving graft-versus-leukemia effects.Science translational medicine · 2023Article
- Planning GvHD preemptive therapy: risk factors, biomarkers, and prognostic scores.Hematology. American Society of Hematology. Education Program · 2023Article
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Authors and funding
34 authors at 5 institutions in 2 countries.
Funding
Abstract
Intestinal epithelial cells (IECs) are implicated in the propagation of T-cell-mediated 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-recruiting chemokines and major histocompatibility complex (MHC) class II molecules, which amplify and sustain alloreactive T-cell responses. Alloreactive T-cell-produced 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.