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Updated: Jun 12, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
RIPK4 promotes oxidative stress and ferroptotic death through the downregulation of ACSM1
Jing Zhang1, Yuehan Wei2, Yangbo Yue1
1Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Abstract:
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.
Insights
Receptor-interacting protein kinase 4 (RIPK4) regulates cell death in response to oxidative stress. RIPK4 activation promotes ferroptosis, a cell death pathway, and its inhibition protects against kidney injury.
Area of Science:
- Cell Biology
- Biochemistry
- Pathology
Background:
- Cell fate is critically determined by responses to reactive oxygen species (ROS) and oxidative stress.
- Excessive lipid peroxidation triggers ferroptosis, a distinct cell death pathway.
- The precise molecular mechanisms linking ROS to specific cellular fates are not fully understood.
Purpose of the Study:
- To elucidate the role of receptor-interacting protein kinase 4 (RIPK4) in oxidative stress-induced cell death.
- To investigate the molecular mechanisms by which RIPK4 influences ferroptosis.
- To explore the therapeutic potential of targeting RIPK4 in acute kidney injury.
Main Methods:
- Utilized siRNA screening to identify key kinases in oxidative stress response.
- Investigated RIPK4 activation and kinase activity upon ROS induction.
- Employed RNA sequencing and lipidome analysis to identify downstream targets and metabolic changes.
- Assessed the protective effects of RIPK4 ablation in mouse models of acute kidney injury.
Main Results:
- RIPK4 was identified as crucial for oxidative stress and ferroptotic cell death, requiring its kinase activity.
- RIPK4 deficiency protected mice from cisplatin-induced and ischemia/reperfusion-induced acute kidney injury.
- RIPK4 deficiency compromised the cisplatin-induced decrease in acyl-CoA synthetase medium-chain (ACSM) family members, particularly ACSM1.
- ACSM1 suppression enhanced oxidative stress and ferroptosis, while its overexpression conferred resistance by accumulating monounsaturated fatty acids and reducing polyunsaturated fatty acids (PUFAs).
Conclusions:
- RIPK4 is a key regulator of oxidative stress and ferroptosis, with implications for various human pathologies.
- The RIPK4-ACSM1 axis influences PUFA metabolism and ferroptosis, revealing a novel mechanism in oxidative stress-induced cell death.
- Targeting the RIPK4-ACSM1 pathway may offer therapeutic strategies for conditions involving ferroptosis and kidney injury.
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