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journal article·2025-12Open access

Lactate Activates the HCAR1/β‐Arrestin2/PP2A Signaling Axis to Mediate STAT1/2 Dephosphorylation and Drive Osteosarcoma Progression

Zhitao Han, Qi Jia, Guangjian Bai, Zhao Li, Jin Zeng, Zhenhua Wang, Jing Zhang, Jiashi Cao, Baoquan Xin, Yonggang Liu, Jingyu Shen, Lining Wang, Xing Huang, Chunlei Zhang, Kai Tong, Fenglei Dai, Yajie Zhang, Weina Zhu, Songyi Cheng, Yuanming Chen, Xinghai Yang, Guanghui Chen, Zhenhua Zhou, Yong Ma, Weibo Liu, Ting Wang, Tielong Liu

Advanced Science· Volume 12· Issue 45
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Source abstract

Abstract

Abstract The “Warburg effect”, a hallmark of Osteosarcoma(OS), results in lactate accumulation due to aerobic glycolysis. The role and underlying mechanisms of lactate in OS are not well understood. Herein, the lactate‐activated hydroxycarboxylate receptor 1(HCAR1) is found to promote OS progression via inhibiting the transcription of anti‐oncogene downstream of STAT1/2. The phosphorylation level of STAT1/2 holds considerable significance for transcriptional activity. In this study, protein phosphatase 2A(PP2A) is identified as the tyrosine phosphatase of STAT1/2. Lactate‐activated HCAR1, facilitating PP2A interaction with phosphorylated STAT1/2 via β‐Arrestin 2, resulting in STAT1/2 dephosphorylation, a key process linked to the aggressive behavior of OS. Using PP2A inhibitor Endothall can abolish the dephosphorylation effect of HCAR1 on STAT1/2, inhibit cancer cell proliferation, migration, and cell cycle, and promote apoptosis. Moreover, the combination of Endothall and Cisplatin is high synergistic in treating OS. In conclusion, the study elucidates the pro‐oncogenic role of lactate‐activated HCAR1 in OS.
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Research context

OpenAlex topics: Histone Deacetylase Inhibitors Research · Cancer, Hypoxia, and Metabolism · Protein Degradation and Inhibitors

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

Affiliations

School of Integrated Chinese and Western Medicine Nanjing University of Chinese Medicine Nanjing Jiangsu 210023 China

Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine Nanjing Jiangsu 210022 China

Department of Orthopaedic Oncology The Second Affiliated Hospital of Naval Medical University Shanghai 200003 China

School of Health Science and Engineering University of Shanghai for Science and Technology Shanghai 200090 China

Department of Orthopedics The First Affiliated Hospital of Nanchang University Nanchang Jiangxi 330006 China

Department of Centre for Translational Medicine The Second Affiliated Hospital of Naval Medical University Shanghai 200003 China

Oncology Department Kunshan Hospital of Chinese Medicine Suzhou Jiangsu 215301 China

Department of Orthopedics Shanghai Pudong Hospital Fudan University Pudong Medical Center Shanghai 200127 China

Central Laboratory Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine Nanjing Jiangsu 210022 China

Department of Orthopedics Second Affiliated Hospital of Guangxi Medical University Nanning Guangxi 530005 China

Department of Orthopaedics Peking University Third Hospital Beijing 100191 China

Yancheng TCM Hospital Affiliated to Nanjing University of Chinese Medicine Yancheng TCM Hospital Yancheng Jiangsu 224002 China

Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease Wuxi TCM Hospital Affiliated to Nanjing University of Chinese Medicine Wuxi Jiangsu 214071 China

Department of Orthopaedics The Fourth Medical Centre Chinese PLA General Hospital Beijing 100853 China

Funding

National Natural Science Foundation of China · Shanghai Rising-Star Program

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