RIPK4 promotes oxidative stress and ferroptotic death through the downregulation of ACSM1.
Jing Zhang, Yuehan Wei, Yangbo Yue, Huike Jiao, Yan Wu, Wan Fu, Keng-Mean Lin, Christopher Lu, Shan Mou, Qing Zhong
Author Information
Jing Zhang: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. ORCID
Yuehan Wei: Department of Nephrology, Molecular Cell Lab for Kidney Disease, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Yangbo Yue: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Huike Jiao: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. ORCID
Yan Wu: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Wan Fu: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Keng-Mean Lin: Division of Nephrology, Department of Internal Medicine and the Graduate Program in Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8856.
Christopher Lu: Division of Nephrology, Department of Internal Medicine and the Graduate Program in Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8856.
Shan Mou: Department of Nephrology, Molecular Cell Lab for Kidney Disease, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Qing Zhong: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. ORCID
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.
