- |||||||||| Review, Journal: PANoptosis as a drug discovery framework: integrating cell death architecture with clinical translation. (Pubmed Central) - Apr 19, 2026
By integrating mechanistic insights with translational pharmacology, this review positions PANoptosis as both a therapeutic target and an adjuvant framework, outlining how its selective modulation could transform the management of infectious, inflammatory, oncologic, and neurodegenerative diseases. Schematic representation of major human disease categories associated with dysregulated PANoptosis.
- |||||||||| cisplatin / Generic mfg.
Tubular Litaf promotes necroptosis by inhibiting Ripk1 ubiquitination in acute kidney injury (Research Zone) - Apr 13, 2026 - Abstract #ERA2026ERA_2491; Method First, two AKI models induced by ischemia/reperfusion injury (I/RI) or cisplatin in C57BL/6J mice were established, while a murine TEC line (TCMK1) was exposed to hypoxia/reoxygenation (H/R) or cisplatin treatment in vitro...Our findings suggest that Litaf could be a promising therapeutic target to alleviate TECs necroptosis and AKI. Image Schematic illustration of the mechanism underlying tubular necroptosis during AKI.
- |||||||||| Journal: RIPK1 as a potential target to augment DC efficacy in tumor immunotherapy. (Pubmed Central) - Mar 19, 2026
Furthermore, this Ripk1 knocked DCs vaccine was employed to treat the tumor carry mice and it can effectively inhibit tumor growth compared with the wild type DCs vaccine. RIPK1 is expected to become a new target for improving the efficacy of DC vaccines.
- |||||||||| Journal, IO biomarker: Polo-like kinase 1 suppresses lung adenocarcinoma immunity through necroptosis. (Pubmed Central) - Mar 10, 2026
These findings suggest that PLK1 plays a critical role in LA progression by regulating necroptosis and immune infiltration, and may serve as a potential therapeutic target for immunotherapy. Furthermore, PLK1 expression can be used as a prognostic biomarker for LA patients.
- |||||||||| eclitasertib (SAR443122) / Sanofi, oditrasertib (DNL788) / Denali Therap, Sanofi
Review, Journal: Small-molecule modulators of the necroptotic pathway: A medicinal chemistry perspective. (Pubmed Central) - Feb 11, 2026 Despite these advancements, the field continues to face challenges, particularly the need for chemical scaffold design and therapeutic strategies to address two longstanding challenges: off-target effects and enhancing blood-brain barrier (BBB) penetration. This review systematically summarizes the development history of regulators targeting this pathway, covering emerging multitarget inhibitors, bifunctional molecules, and AI-driven drug design progress, laying an important foundation for related drug discovery research.
- |||||||||| GSK2982772 / GSK, Kineret (anakinra) / SOBI
Review, Journal: Treatment of Inflammatory Bowel Disease with Drugs Targeting PANoptosis: A Comprehensive Review. (Pubmed Central) - Jan 28, 2026 Furthermore, RIPK1 inhibitors such as GSK2982772 have failed to meet primary endpoints in Phase 2 trials. PANoptosis is a "hot" therapeutic target, but successful treatment likely requires combination therapies or "PANoptosome" specific modulators rather than single-pathway inhibition.
- |||||||||| belnacasan (VX-765) / Vertex, emricasan (IDN 6556) / Amerimmune, disulfiram / Generic mfg.
Preclinical, Journal: Andrographolide-induced PANoptosis underlies its multiple organ toxicity in mice. (Pubmed Central) - Jan 24, 2026 In addition, RIPK1 inhibition (by Nec-1) partially reduced cell death, confirming RIPK1-dependent necroptosis as a minor contributor. In conclusion, our data establish PANoptosis as an important mechanism of Andro-induced organ injury, providing a mechanistic framework for Andro's dichotomous bioactivity, informing evidence-based dosing strategies to maximize therapeutic efficacy while mitigating toxicity risks in clinical practice.
- |||||||||| Journal: Synthesis and anti-acute ischemic stroke effect of quinazoline-benzothiazole RIPK1 inhibitors. (Pubmed Central) - Jan 23, 2026
In a middle cerebral artery occlusion (MCAO) rat model, compound 2 significantly improved neurological function scores, reduced cerebral infarct volume, ameliorated serum biochemical profiles, and exhibited low acute toxicity in mice. These results indicate that compound 2 is a potent RIPK1 inhibitor with potential as a therapeutic agent for AIS.
- |||||||||| Review, Journal: Receptor-Interacting Protein Kinase 1 (RIPK1): A Potential Therapeutic Target in Ischemic Stroke. (Pubmed Central) - Jan 15, 2026
We then dissect the multifaceted mechanisms by which RIPK1 participates in ischemic stroke pathology, including its roles in cell death, neuroinflammation, and blood-brain barrier integrity, as well as its potential as a diagnostic indicator for ischemic brain injury. Finally, we present a concise overview of the development status of RIPK1 inhibitors, which covers preclinical candidates and clinical trial-stage agents, aiming to inform future research endeavors and guide clinical translation for ischemic stroke treatment.
- |||||||||| RIPK1 DRIVES LYSOSOMAL-STRESS () - Jan 10, 2026 - Abstract #ADPD2026ADPD_2823;
By responding to lysosomal stress through a novel non-canonical signaling mechanism, RIPK1 promotes microglial proliferation, inflammatory activation, and lipid dysregulation. These findings identify RIPK1 as a promising therapeutic target and support precision-medicine strategies using RIPK1 inhibitors in disorders where these hyperinflammatory lipid-associated microglia contribute to neurodegeneration.
- |||||||||| eclitasertib (SAR443122) / Sanofi
Anti-inflammatory effect of RIPK1 inhibitor eclitasertib in inflamed human gut tissue (Poster Exhibition) - Jan 6, 2026 - Abstract #ECCOIBD2026ECCO_IBD_1316; The difficulty of reaching statistically relevant thresholds for observed effects might be based on limited sample size, high inter-donor variation but also by intra-donor variation of the biopsies linked to the experimental model. The findings support further investigation of eclitasertib in populations with IBD.
- |||||||||| Impact of innate immune memory on MDS progression by TET2-driven inflammation (OCCC - West Halls B3-B4) - Nov 4, 2025 - Abstract #ASH2025ASH_1963;
VavTet2fl/fl mice markedly expand myeloid-biased progenitors at the expenseof the erythroid- and megakaryocyte-biased progenitors, resembling MDS-like disease progression.Intriguingly, inhibiting inflammation by RIPK1 inactivation dampens deleterious effects on hematopoiesis.Collectively, these results provide insight into how, in a physiologically relevant infection model, TET2deficiency impairs immune responses and drives inflammation. We further show that prior innateimmune activation with MPLA improves infection response but impairs hematopoiesis in a RIPK1-dependent manner.
- |||||||||| SM-164 / Ascenta, sunitinib / Generic mfg.
Journal: SPOP mediates apoptosis and protects against necroptosis by regulating ubiquitination of RIPK1 and RIPK3. (Pubmed Central) - Oct 22, 2025 Based on these findings, a combination therapy using the second mitochondria-derived activator of caspases (Smac) mimetic SM164 and sunitinib was developed, demonstrating a more pronounced efficacy than sunitinib monotherapy, and this sensitizing effect was dependent on the expression level of RIPK1. These results suggest that the combination of Smac mimetics with tyrosine kinase inhibitors holds potential clinical value for tumors with dysregulated SPOP/RIPK1/RIPK3 signaling.
- |||||||||| Journal: ATR-mediated phosphorylation of RIPK1 inhibits DNA damage-induced necroptosis. (Pubmed Central) - Aug 23, 2025
This was characterized by heightened necroptosis activation, reduced cell viability, and increased apoptosis. These findings expand our understanding of the interaction between DNA damage and cell death regulation and may aid in developing therapeutic drugs to enhance DNA damage-induced tumor necroptosis and improve chemosensitivity.
- |||||||||| Journal: Modeling the HLH immune synapse uncovers critical roles for IS termination, cytokine intensity, and target cell death. (Pubmed Central) - Jul 31, 2025
By quantifying CTL-IS duration, cytokine production, and mode of cell death, we modeled multiple HLH contributors and their interactions, and identified three HLH mechanistic categories: impaired IS termination, intense CTL cytokine production, and inflammatory target cell death. Integrating the inputs and outcomes of a hyperinflammatory CTL-IS may provide a useful framework for understanding, predicting, or treating HLH in its many forms.
- |||||||||| Journal: Targeting RIPK1-mediated necroptosis, oxidative stress, and ferroptosis: A novel multitarget therapy for ischemic stroke. (Pubmed Central) - Jul 10, 2025
In vivo studies showed that 23a markedly reduced cerebral infarction volume and improved neurological function scores in transient middle cerebral artery occlusion (tMCAO) model, outperforming edaravone, and demonstrated multi-target effects against oxidative stress, necroptosis, and ferroptosis in the ischemic penumbra tissue. These findings collectively highlight 23a as a promising triple-target lead compound for ischemic stroke therapy, warranting further optimization and development.
- |||||||||| RG6287 / Roche
Journal: Data Science-Guided Development of Deoxyfluorination Reagents with Enhanced Reactivity, Practicality, and Safety. (Pubmed Central) - Jul 9, 2025 We developed predictive models to optimize sulfonyl fluoride reagents for the deoxyfluorination of a key intermediate used in the synthesis of RIPK1 inhibitor GDC-8264. The top-performing reagents demonstrated broad applicability across diverse alcohol substrate classes, including complex natural products and active pharmaceutical ingredients, highlighting the power of data science-enabled approaches in reagent development.
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