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journal article·2025-02Open access

Suppression of Hepatocyte Ferroptosis via USP19‐Mediated Deubiquitination of SLC7A11 in Ischemia‐Free Liver Transplantation

Jinghong Xu, Shirui Chen, Di Liu, Qi Zhang, Tao Luo, Jiaxing Zhu, Liang Zhou, Yuan Lin, Hongyu Pan, Yichao Chen, Qiang Zhao, Tielong Wang, Schlegel Andrea, Björn Nashan, Tullius G. Stefan, Changjie Cai, Jun Cui, Xiaoshun He, Zhiyong Guo

Advanced Science· Volume 12· Issue 6
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Source abstract

Abstract

Abstract Ischemia‐free liver transplantation (IFLT) is developed as a novel clinical approach to avoid ischemia‐reperfusion injury (IRI). This study aims to identify the most distinguished programmed cell death pathway in grafts undergoing IFLT versus conventional liver transplantation (CLT) and to explore the underlying mechanism. Ferroptosis is the most distinct programmed cell death form between IFLT and CLT grafts. Among various cell death inhibitors, the ferroptosis inhibitor (Ferrostain‐1) is the most effective one to prevent hepatocytes from damage induced by oxygen deprivation/reoxygenation (OGD/R). Hepatocyte ferroptosis is significantly alleviated in IFLT versus CLT grafts in both human beings and pigs. Ubiquitination enzyme screening identifies augmented amounts of ubiquitin‐specific protease 19 (USP19) in IFLT versus CLT grafts. The upregulation of USP19 in the grafts is correlated with reduced pathological Suzuki's score, lower post‐transplant peak liver enzyme level, and less early allograft dysfunction in liver transplant recipients. USP19 overexpression mitigates post‐transplant liver injury in mice. Mechanistically, USP19 inhibits the degradation of solute carrier family 7 member 11 (SLC7A11) by removing its K63‐linked ubiquitin chains. Notably, USP19 overexpression reduces ferroptosis and IRI in a SLC7A11‐dependent manner in mice. Collectively, USP19‐mediated suppression of hepatocyte ferroptosis via deubiquitinating SLC7A11 is a key mechanism by which IFLT abrogates graft IRI.
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Research context

OpenAlex topics: Ferroptosis and cancer prognosis · MicroRNA in disease regulation · Epigenetics and DNA Methylation

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Organ Transplant Center The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 China

Department of Anesthesiology The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 China

Guangdong Provincial Key Laboratory of Organ Medicine Guangzhou Guangdong 510080 China

Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation) Guangzhou Guangdong 510080 China

Department of Thyroid and Breast Surgery The Second Affiliated Hospital of Anhui Medical University Hefei Anhui 230601 China

Zhongshan School of Medicine Sun Yat‐sen University Guangzhou Guangdong 510080 China

School of Life Sciences Sun Yat‐sen University Guangzhou Guangdong 510080 China

Department of Pathology The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 China

Transplantation Center Digestive Disease and Surgery Institute and Department of Immunology Lerner Research Institute, Cleveland Clinic Cleveland Ohio 44113 USA

Organ Transplant Center The First Affiliated Hospital of the University of Science and Technology of China Hefei Anhui 230001 China

Division of Transplant Surgery Brigham and Women's Hospital Harvard Medical School Boston MA 02115 USA

Department of Critical Care The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 China

NHC Key Laboratory of Assisted Circulation Sun Yat‐sen University Guangzhou Guangdong 510080 China

Funding

National Natural Science Foundation of China

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