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Review
. 2023 Oct 26:14:1274654.
doi: 10.3389/fimmu.2023.1274654. eCollection 2023.

RIPK1 and RIPK3 inhibitors: potential weapons against inflammation to treat diabetic complications

Dan Ke #  1   2 , Zhen Zhang #  2   3 , Jieting Liu #  1   2 , Peijian Chen  1   2 , Yucen Dai  1   2 , Xinhai Sun  4 , Yanhui Chu  2 , Luxin Li  1   2
Affiliations
Review

RIPK1 and RIPK3 inhibitors: potential weapons against inflammation to treat diabetic complications

Dan Ke et al. Front Immunol. .

Abstract

Diabetes mellitus is a metabolic disease that is characterized by chronic hyperglycemia due to a variety of etiological factors. Long-term metabolic stress induces harmful inflammation leading to chronic complications, mainly diabetic ophthalmopathy, diabetic cardiovascular complications and diabetic nephropathy. With diabetes complications being one of the leading causes of disability and death, the use of anti-inflammatories in combination therapy for diabetes is increasing. There has been increasing interest in targeting significant regulators of the inflammatory pathway, notably receptor-interacting serine/threonine-kinase-1 (RIPK1) and receptor-interacting serine/threonine-kinase-3 (RIPK3), as drug targets for managing inflammation in treating diabetes complications. In this review, we aim to provide an up-to-date summary of current research on the mechanism of action and drug development of RIPK1 and RIPK3, which are pivotal in chronic inflammation and immunity, in relation to diabetic complications which may be benefit for explicating the potential of selective RIPK1 and RIPK3 inhibitors as anti-inflammatory therapeutic agents for diabetic complications.

Keywords: diabetes; diabetic complications; inflammation; receptor interacting protein kinase; regulatory cell death.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Mechanism of NF-κB activation by RIPK1. TNF-α binds to the membrane receptor TNFR1 and recruits TRADD, TRAF2, cIAP1/2 and RIPK1 to initiate the formation of complex I, which is composed of the ubiquitin chain assembly complex LUBAC and the E3 ubiquitin ligase. In complex I, LUBAC works with the E3 ubiquitin ligase to add the K63 ubiquitin chain to RIPK1, which binds to NEMO and recruits the IKK complex, activating the IκB protein and releasing NF-κB. Subsequent translocation of NF-κB to the nucleus promotes the transcription of pro-inflammatory genes and increases the expression of cytosolic inflammatory mediators.
Figure 2
Figure 2
Mechanism of RIPK1 and RIPK3 in apoptosis and necroptosis. TNF-α binds to the membrane receptor TNFR1, recruiting TRADD, TRAF2, cIAP1/2 and RIPK1, initiating the formation of pro-survival complex I. Caspase-8 is activated and RIPK1 and TRADD in complex I bind to FADD, forming complex II a with activated caspase-8, promoting apoptosis. When caspase-8 activation is inhibited, RIPK1 and RIPK3 interact via RHIM isoforms, recruiting MLKL and forming complex II b, leading to necroptosis.
Figure 3
Figure 3
RIPK1 and RIPK3’s complex crosstalk in inflammation. TNF-α binds to the membrane receptor TNFR1 and recruits TRADD, TRAF2, cIAP1/2 and RIPK1 to initiate complex I formation. RIPK1, which is involved in complex I formation, is a key protein in both complex IIa and complex IIb. Ubiquitination of RIPK1 plays an essential role in NF-κB signaling. Caspase-8, when activated, forms complex IIa with RIPK1, leading to apoptosis, whereas inhibition of caspase-8 promotes necrotic apoptosis by forming complex IIb. RIPK3 can also independently induce the formation of inflammasome.
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The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Local Colleges and Universities Talent Development Funding from Heilongjiang Provincial Department of Finance (No. 2020GSP09), the Natural Science Foundation of Heilongjiang Province (No. LH2022H099), the Basic Scientific Research Project of University belongs to Heilongjiang (No. 2021-KYYWF-0519), the Heilongjiang Provincial Key Research and Development Program (No. GZ20210121), the Torch Program of Mudanjiang Medical University (No. 2022-MYHJ-003) and the Project of Young Innovative Talents Training Program of Regular Undergraduate Colleges and Universities in Heilongjiang Province (No. UNPYSCT-2020064).