P2, N=174, Terminated, Sanofi | Trial completion date: Sep 2025 --> Nov 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Sep 2025 --> Nov 2024; The study was terminated as it did not meet its primary and key secondary endpoints

A recent paper in Immunity describes a small molecule inducing the proteolytic degradation of RIPK1. In preclinical experiments, this RIPK1 inhibitor improved the anticancer efficacy of radiotherapy, immunotherapy (with PD-1 blockade) and radioimmunotherapy (with CTLA-4 blockade).

RIP1 regulates chondrocyte apoptosis through NF-κB signaling. Inhibition of RIP1 provides a novel therapeutic approach for OA therapy.

Furthermore, DHHC5 is amplified by fatty acid in the livers of mice with metabolic dysfunction-associated steatohepatitis, contributing to increased RIPK1 cytotoxicity observed in this condition. Our findings reveal that ubiquitination-dependent palmitoylation licenses RIPK1 kinase activity to induce downstream cell death signaling and suggest RIPK1 palmitoylation as a feasible target for inflammatory diseases.

In addition, the RIPK1, RIPK3, MLKL, and caspase-8 expression levels were significantly decreased, evidenced improvement of intestinal necroptosis by VNP. Hence, VNP potently prevents intestinal injury induced by 5-FU by modulating Keap1/Nrf2/HO-1, NF-κB/TLR4/SOCS3, and RIPK1/RIPK3/MLKL signals.

P1, N=25, Completed, AbbVie | Active, not recruiting --> Completed

P2, N=30, Active, not recruiting, AbbVie | Trial completion date: Sep 2025 --> Dec 2024 | Trial primary completion date: Sep 2025 --> Dec 2024

P2, N=404, Not yet recruiting, Genentech, Inc.

P2, N=30, Active, not recruiting, AbbVie | Recruiting --> Active, not recruiting | Trial completion date: May 2026 --> Sep 2025 | Trial primary completion date: May 2026 --> Sep 2025

Site-specific depletion of O-GlcNAcylation on RIPK1 affects the formation of the RIPK1/FADD/Caspase 8 complex, leading to increased sunitinib sensitivity in RCC. Our data highlight the significance of aberrant RIPK1 O-GlcNAcylation in the development of sunitinib resistance and indicate that targeting RIPK1 O-GlcNAcylation could be a promising therapeutic strategy for RCC.

Notably, [18F]WL1 showed significant potential in imaging the alterations of RIPK1 in a rat brain of tumor necrosis factor α-induced systemic inflammatory response syndrome model. These findings may pave the way for the future design of potent RIPK1 PET ligands.

Moderate in vivo stability was noted for [18F]WL8 in mouse brains with 35.2 % of the parent fraction remaining after 30 min post-administration. Altogether, our work broadens the landscape and offers a new chemotype for RIPK1 PET ligand development.

P1, N=80, Completed, Sironax Aus Pty Ltd | Recruiting --> Completed

P1, N=10, Completed, Sironax Aus Pty Ltd | Not yet recruiting --> Completed

P1, N=25, Active, not recruiting, AbbVie | Recruiting --> Active, not recruiting

A change in the structural rigidity is also suggested by the observation of weakened signals for mouse RIPK3 upon mixing with RIPK1 to form the RIPK1/RIPK3 complex fibrils. Our results provide vital information to understand the interactions between different proteins with RHIM, which will help us further comprehend the regulation mechanism in cell necroptosis.

5Z treatment enhances IAV-induced cell death and slightly reduces the inflammatory response in the lungs of H1N1 virus-infected mice and prolongs the survival of IAV-infected mice. Our study provides evidence that IAV activates TAK1 to suppress RIPK1-dependent apoptosis and necroptosis, and that RIPK3 is required for IAV-induced necroptosis but not apoptosis in epithelial cells.

We demonstrate that PERK mediated UPR regulates senescence reversal and its inhibition can be exploited as potential seno-therapeutic option in glioblastoma.

P1, N=24, Recruiting, AbbVie | Not yet recruiting --> Recruiting

Unlike in many other cell types (e.g., epithelial, and immune), RIPK1 is not required for cell death regulation in β-cells under physiological conditions or diabetic challenges. Moreover, in vivo and in vitro evidence suggest that pancreatic β-cells do not undergo necroptosis but mainly caspase-dependent death in response to TNF. Last, our results show that β-cells have a distinct mode of regulation of TNF-cytotoxicity that is independent of RIPK1 and that may be highly dependent on cFLIP.

The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Consequently, these signal inhibitors sensitize cells to the PROTAC-induced apoptosis. These results suggest that various cell-intrinsic signaling pathways spontaneously counteract chemically induced target degradation at multiple steps, which could be liberated by specific inhibitors.

P1, N=24, Not yet recruiting, AbbVie

This assay enabled the characterization of RIPK1 target engagement by various RIPK1 inhibitors for both human and mouse RIPK1 in live cells. Our developed fluorescent probe displacement assays offer a sensitive and high-throughput approach to identify RIPK1 inhibitors based on both biochemical and cellular activities.

Our results suggest that OTUD6B is a promising clinical target for LUAD treatment and that targeting OTUD6B may constitute an effective anti-LUAD strategy.

In line with this finding, RUBCNL expression limits assembly of RIPK1-TNFRSF1A/TNFR1 complex I, suggesting that complex formation between RUBCNL and RIPK1 represses TNF signaling. These results provide new insights into the crosstalk between the RIPK1-mediated cell death and autophagy machineries and suggest that RUBCNL, due to its functional duality in autophagy and apoptosis/necroptosis, could be targeted to improve the therapeutic efficacy of MSCs.

This promoted ICD, antitumor immunity, and durable treatment responses. Consequently, targeting RIPK1 by PROTACs emerges as a promising approach to overcome radio- or immunotherapy resistance and enhance anticancer therapies.

P2, N=40, Recruiting, AbbVie | Trial primary completion date: May 2025 --> May 2026

P1, N=114, Completed, Sironax Aus Pty Ltd | Recruiting --> Completed

The cell counting kit-8 was used to detect the effect of Tan IIA on the activity of cisplatin in chemoresistant HNSCC cells through a series of in vitro experiments...This study is the first to demonstrate the clinical value and role of FADD and RIPK1 in the treatment of HNSCC. This work establishes the proapoptotic effects of Tan IIA and its potential to enhance chemosensitivity in HNSCC by modulating the RIPK1-FADD-Caspase 8 complex.

We propose that OSW-1 can induce necroptosis through the RIPK1/RIPK3/MLKL signaling pathway, and that this effect is mediated by the RIPK1-p62/SQSTM1 complex, in CRC cells. These results provide a theoretical foundation for the use of OSW-1 in the clinical treatment of CRC.

In addition, exposure to pro-inflammatory cytokines IFNγ and TNFα can sensitize resistant GSCs to TAK1 inhibition. Our findings reveal dependency on TAK1 kinase activity as a novel vulnerability in immune-activated cancers, including mesenchymal GBMs that can be exploited therapeutically.

P2, N=305, Terminated, Sanofi | Trial completion date: Jan 2027 --> Mar 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2024 --> Mar 2024; The study was terminated as its Part A did not meet the primary endpoint.

Genetic inactivation of necroptosis ameliorates the progeroid phenotypes in Zmpste24-/- mice. Our findings identify an unconventional nuclear necroptosis pathway resulting from ZMPSTE24 deficiency with pathogenic consequences in progeroid disorder and suggest RIPK1 as a feasible target for prelamin A-associated progeroid disorders.

Moreover, eupatolide was sufficient to upregulate the activation of RIPK1, facilitating the TNF-mediated dual modes of apoptosis and necroptosis. Thus, we propose a novel mechanism by which eupatolide activates the cytotoxic potential of RIPK1 at the TNFR1 level and provides a promising anti-cancer therapeutic approach to overcome TNF resistance.

P2, N=40, Recruiting, AbbVie | Trial completion date: Aug 2025 --> May 2026

P1, N=7, Terminated, Genentech, Inc. | N=40 --> 7 | Trial completion date: Dec 2025 --> Jan 2024 | Recruiting --> Terminated | Trial primary completion date: Dec 2025 --> Jan 2024; Study was terminated for business reasons. There were no safety or efficacy concerns regarding the study or study drug in the decision to terminate the study.

P2, N=380, Recruiting, Eli Lilly and Company | Phase classification: P2a/2b --> P2 | Trial primary completion date: Jun 2024 --> Feb 2026

P1, N=32, Completed, Eli Lilly and Company | Active, not recruiting --> Completed

P1, N=8, Completed, Eli Lilly and Company | Recruiting --> Completed

These results indicate that acetylshikonin activated the RIPK1/RIPK3/MLKL cascade, leading to necroptosis in NSCLC cells. Our findings indicate that acetylshikonin reduces lung cancer cells by promoting G2/M phase arrest and necroptosis.

P2, N=305, Active, not recruiting, Sanofi | Trial completion date: Jul 2025 --> Jan 2027 | Trial primary completion date: Jan 2024 --> Jul 2024

Collectively, our results disclose an inflammatory injury mechanism of human bone marrow derived MSCs based on its morphological and functional alterations in combination with RNA-Seq identification, and a firstly found necroptotic manner of cell death in MSCs sheds new light on revealing the MSC deficits in some inflammatory or immune-mediated diseases with expectations to innovate some potential therapeutics. Our findings also suggest that cell therapy based on MSCs primed with IFN-γ and TNF-α should take this inflammatory injury effect into consideration.