RIPK4

Last update 08 May 2025

Basic Info

Synonyms

ANKK2, ANKRD3, ankyrin repeat domain 3

+ [10]

Introduction

Serine/threonine protein kinase (By similarity). Required for embryonic skin development and correct skin homeostasis in adults, via phosphorylation of PKP1 and subsequent promotion of keratinocyte differentiation and cell adhesion (By similarity). It is a direct transcriptional target of TP63 (PubMed:22197488). Plays a role in NF-kappa-B activation (PubMed:12446564).

100 Clinical Results associated with RIPK4

100 Translational Medicine associated with RIPK4

0 Patents (Medical) associated with RIPK4

125

Literatures (Medical) associated with RIPK4

01 Oct 2024·Proceedings of the National Academy of Sciences

RIPK4 promotes oxidative stress and ferroptotic death through the downregulation of ACSM1

Article

Author: Yue, Yangbo ; Fu, Wan ; Wei, Yuehan ; Wu, Yan ; Lin, Keng-Mean ; Jiao, Huike ; Zhang, Jing ; Mou, Shan ; Lu, Christopher ; Zhong, Qing

One of the most critical axes for cell fate determination is how cells respond to excessive reactive oxygen species (ROS)—oxidative stress. Extensive lipid peroxidation commits cells to death via a distinct cell death paradigm termed ferroptosis. However, the molecular mechanism regulating cellular fates to distinct ROS remains incompletely understood. Through siRNA against human receptor-interacting protein kinase (RIPK) family members, we found that RIPK4 is crucial for oxidative stress and ferroptotic death. Upon ROS induction, RIPK4 is rapidly activated, and the kinase activity of RIPK4 is indispensable to induce cell death. Specific ablation of RIPK4 in kidney proximal tubules protects mice from acute kidney injury induced by cisplatin and renal ischemia/reperfusion. RNA sequencing revealed the dramatically decreased expression of acyl-CoA synthetase medium-chain (ACSM) family members induced by cisplatin treatment which is compromised in RIPK4-deficient mice. Among these ACSM family members, suppression of ACSM1 strongly augments oxidative stress and ferroptotic cell death with induced expression of ACS long-chain family member 4, an important component for ferroptosis execution. Our lipidome analysis revealed that overexpression of ACSM1 leads to the accumulation of monounsaturated fatty acids, attenuation of polyunsaturated fatty acid (PUFAs) production, and thereby cellular resistance to ferroptosis. Hence, knockdown of ACSM1 resensitizes RIPK4 KO cells to oxidative stress and ferroptotic death. In conclusion, RIPK4 is a key player involved in oxidative stress and ferroptotic death, which is potentially important for a broad spectrum of human pathologies. The link between the RIPK4–ASCM1 axis to PUFAs and ferroptosis reveals a unique mechanism to oxidative stress–induced necrosis and ferroptosis.

01 Sep 2024·Molecular Neurobiology

Ripks and Neuroinflammation

Review

Author: Xu, Yue ; Zhang, Lei ; Chen, Wenli ; Lin, Feng ; Liao, Guolei ; Sun, Jiaxing

Neuroinflammation is an immune response in the central nervous system and poses a significant threat to human health. Studies have shown that the receptor serine/threonine protein kinase family (RIPK) family, a popular research target in inflammation, has been shown to play an essential role in neuroinflammation. It is significant to note that the previous reviews have only examined the link between RIPK1 and neuroinflammation. However, it has yet to systematically analyze the relationship between the RIPK family and neuroinflammation. Activation of RIPK1 promotes neuroinflammation. RIPK1 and RIPK3 are responsible for the control of cell death, including apoptosis, necrosis, and inflammation. RIPK1 and RIPK3 regulate inflammatory responses through the release of damage in necroptosis. RIPK1 and RIPK3 regulate inflammatory responses by releasing damage-associated molecular patterns (DAMPs) during necrosis. In addition, activated RIPK1 nuclear translocation and its interaction with the BAF complex leads to upregulation of chromatin modification and inflammatory gene expression, thereby triggering inflammation. Although RIPK2 is not directly involved in regulating cell death, it is considered an essential target for treating neurological inflammation. When the peptidoglycan receptor detects peptidoglycan IE-DAP or MDP in bacteria, it prompts NOD1 and NOD2 to recruit RIPK2 and activate the XIAP E3 ligase. This leads to the K63 ubiquitination of RIPK2. This is followed by LUBAC-mediated linear ubiquitination, which activates NF-KB and MAPK pathways to produce cytokines and chemokines. In conclusion, there are seven known members of the RIPK family, but RIPK4, RIPK5, RIPK6, and RIPK7 have not been linked to neuroinflammation. This article seeks to explore the potential of RIPK1, RIPK2, and RIPK3 kinases as therapeutic interventions for neuroinflammation, which is associated with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), ischemic stroke, Parkinson's disease (PD), multiple sclerosis (MS), and traumatic brain injury (TBI).

20 Aug 2024·Journal of the American Heart Association

Systematic Druggable Genome‐Wide Mendelian Randomization Identifies Therapeutic Targets for Functional Outcome After Ischemic Stroke

Article

Author: Zhu, Li‐Fang ; Dong, Ming‐Hao ; You, Yun‐Fan ; Chu, Yun‐Hui ; Yang, Sheng ; Zhang, Lu‐Yang ; Deng, Gang ; Shang, Ke ; Xiao, Jun ; Pang, Xiao‐Wei ; Zhou, Luo‐Qi ; Qin, Chuan ; Chen, Lian ; Wang, Wei ; Tian, Dai‐Shi

BackgroundStroke is a leading cause of death worldwide, with a lack of effective treatments for improving the prognosis. The aim of the present study was to identify novel therapeutic targets for functional outcome after ischemic stroke .Methods and Results Cis‐expression quantitative trait loci data for druggable genes were used as instrumental variables. The primary outcome was the modified Rankin Scale score at 3 months after ischemic stroke, evaluated as a dichotomous variable (3–6 versus 0–2) and also as an ordinal variable. Drug target Mendelian randomization, Steiger filtering analysis, and colocalization analysis were performed. Additionally, phenome‐wide Mendelian randomization analysis was performed to identify the safety of the drug target genes at the genetic level. Among >2600 druggable genes, genetically predicted expression of 16 genes ( ABCC2 , ATRAID , BLK , CD93 , CHST13 , NR1H3 , NRBP1 , PI3 , RIPK4 , SEMG1 , SLC22A4 , SLC22A5 , SLCO3A1 , TEK , TLR4 , and WNT10B ) demonstrated the causal associations with ordinal modified Rankin Scale ( P <1.892×10 −5 ) or poor functional outcome (modified Rankin Scale 3–6 versus 0–2, P <1.893×10 −5 ). Steiger filtering analysis suggested potential directional stability ( P <0.05). Colocalization analysis provided further support for the associations between genetically predicted expression of ABCC2 , NRBP1 , PI3 , and SEMG1 with functional outcome after ischemic stroke. Furthermore, phenome‐wide Mendelian randomization revealed additional beneficial indications and few potential safety concerns of therapeutics targeting ABCC2 , NRBP1 , PI3 , and SEMG1 , but the robustness of these results was limited by low power. ConclusionsThe present study revealed 4 candidate therapeutic targets for improving functional outcome after ischemic stroke, while the underlying mechanisms need further investigation.

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RIPK4

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