Affiliation:
1. Division of Hepatobiliary and Pancreatic Surgery Department of Surgery The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang Province 310003 China
2. NHC Key Laboratory of Combined Multi‐organ Transplantation Hangzhou Zhejiang Province 310003 China
3. Key Laboratory of the Diagnosis and Treatment of Organ Transplantation Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer Chinese Academy of Medical Sciences (2019RU019) Hangzhou Zhejiang Province 310003 China
4. Key Laboratory of Organ Transplantation Research Center for Diagnosis and Treatment of Hepatobiliary Diseases Hangzhou Zhejiang Province 310003 China
Abstract
AbstractHepatocellular carcinoma (HCC) is one of the most common malignancies with poor prognosis, and novel treatment strategies are urgently needed. Mitochondria are key regulators of cellular homeostasis and potential targets for tumor therapy. Here, the role of mitochondrial translocator protein (TSPO) in the regulation of ferroptosis and antitumor immunity is investigated and the potential therapeutic implications for HCC are assessed. TSPO is highly expressed in HCC and associated with poor prognosis. Gain‐ and loss‐of‐function experiments present that TSPO promotes HCC cell growth, migration, and invasion in vitro and in vivo. In addition, TSPO inhibits ferroptosis in HCC cells via enhancing the Nrf2‐dependent antioxidant defense system. Mechanistically, TSPO directly interacts with P62 and interferes with autophagy, leading to the accumulation of P62. The P62 accumulation competes with KEAP1, preventing it from targeting Nrf2 for proteasomal degradation. Furthermore, TSPO promotes HCC immune escape by upregulating PD‐L1 expression through Nrf2‐mediated transcription. Notably, TSPO inhibitor PK11195 combines with anti‐PD‐1 antibody showing a synergistic anti‐tumor effect in a mouse model. Overall, the results demonstrated that mitochondrial TSPO promotes HCC progression by inhibiting ferroptosis and antitumor immunity. Targeting TSPO can be a promising new strategy for HCC treatment.
Funder
Health Commission of Zhejiang Province
National Natural Science Foundation of China
Subject
General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)
Cited by
12 articles.
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