2. Academic Validation
  3. Cytoplasmic HMGB1 induces renal tubular ferroptosis after ischemia/reperfusion

Cytoplasmic HMGB1 induces renal tubular ferroptosis after ischemia/reperfusion

  • Int Immunopharmacol. 2023 Feb 1;116:109757. doi: 10.1016/j.intimp.2023.109757.
Zhi Zhao 1,  Guoli Li 2,  Yuxi Wang 2,  Yinzheng Li 2,  Huzi Xu 2,  Wei Liu 1,  Wenke Hao 1,  Ying Yao 3,  Rui Zeng 4
Affiliations

Affiliations

  • 1 Department of Nephrology, Guangdong Provincial Geriatrics Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China.
  • 2 Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
  • 3 Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: yaoyingkk@126.com.
  • 4 Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: zengrui@tjh.tjmu.edu.cn.
PMID: 36731154 DOI: 10.1016/j.intimp.2023.109757
Abstract

As a damage-associated molecular pattern molecule, high-mobility group box 1 (HMGB1) is well-studied and is released from injured tubular epithelial cells to trigger cell death. However, the role of intracellular HMGB1 induced cell death during acute kidney injury (AKI) is poorly understood. We showed that cytosolic HMGB1 induced Ferroptosis by binding to acyl-CoA synthetase long-chain family member 4 (ACSL4), the driver of Ferroptosis, following renal ischemia/reperfusion (I/R). Both mouse and human kidneys with acute tubular injury were characterized by nucleocytoplasmic translocation of HMGB1in tubular cells. Pharmacological inhibition of HMGB1 nucleocytoplasmic translocation and deletion of HMGB1 in tubular epithelial cells in mice inhibited I/R-induced AKI, tubular Ferroptosis, and inflammation compared to those in controls. Co-immunoprecipitation and serial section staining confirmed the interaction between HMGB1 and ACSL4. Taken together, our results demonstrated that cytoplasmic HMGB1 is essential for exacerbating inflammation-associated cellular injury by activating renal tubular Ferroptosis via ACSL4 after I/R injury. These findings indicate that cytoplasmic HMGB1 is a regulator of Ferroptosis and a promising therapeutic target for AKI.

Keywords

ACSL4; AKI; Ferroptosis; HMGB1; Inflammation; Ischemia-reperfusion injury.

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