2. Academic Validation
  3. Lactate Activates the HCAR1/β-Arrestin2/PP2A Signaling Axis to Mediate STAT1/2 Dephosphorylation and Drive Osteosarcoma Progression

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

  • Adv Sci (Weinh). 2025 Sep 16:e06214. doi: 10.1002/advs.202506214.
Zhitao Han 1 2,  Qi Jia 3,  Guangjian Bai 4,  Zhao Li 4,  Jin Zeng 5,  Zhenhua Wang 6,  Jing Zhang 3,  Jiashi Cao 3,  Baoquan Xin 3,  Yonggang Liu 3,  Jingyu Shen 7,  Lining Wang 1 2,  Xing Huang 8,  Chunlei Zhang 2,  Kai Tong 2,  Fenglei Dai 2,  Yajie Zhang 9,  Weina Zhu 9,  Songyi Cheng 2,  Yuanming Chen 10,  Xinghai Yang 3 4,  Guanghui Chen 11,  Zhenhua Zhou 3,  Yong Ma 1 12 13,  Weibo Liu 14,  Ting Wang 3,  Tielong Liu 3 4
Affiliations

Affiliations

  • 1 School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
  • 2 Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210022, China.
  • 3 Department of Orthopaedic Oncology, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China.
  • 4 School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200090, China.
  • 5 Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
  • 6 Department of Centre for Translational Medicine, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China.
  • 7 Oncology Department, Kunshan Hospital of Chinese Medicine, Suzhou, Jiangsu, 215301, China.
  • 8 Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 200127, China.
  • 9 Central Laboratory, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210022, China.
  • 10 Department of Orthopedics, Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530005, China.
  • 11 Department of Orthopaedics, Peking University Third Hospital, Beijing, 100191, China.
  • 12 Yancheng TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Yancheng TCM Hospital, Yancheng, Jiangsu, 224002, China.
  • 13 Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease, Wuxi TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi, Jiangsu, 214071, China.
  • 14 Department of Orthopaedics, The Fourth Medical Centre, Chinese PLA General Hospital, Beijing, 100853, China.
PMID: 40956299 DOI: 10.1002/advs.202506214
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.

Keywords

HCAR1; STAT1/2; lactate; osteosarcoma; β‐Arrestin 2.

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