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

doi:10.1002/advs.202506214

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 ChenXinghai Yang, Guanghui Chen, Zhenhua Zhou, Yong Ma, Weibo Liu, Ting Wang, Tielong Liu

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	e06214
Journal	Advanced Science
Volume	12
Issue number	45
DOIs	https://doi.org/10.1002/advs.202506214
Publication status	Published - 4 Dec 2025
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.

Keywords

HCAR1
lactate
osteosarcoma
STAT1/2
β-Arrestin 2

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Han, Z., Jia, Q., Bai, G., Li, Z., Zeng, J., Wang, Z., Zhang, J., Cao, J., Xin, B., Liu, Y., Shen, J., Wang, L., Huang, X., Zhang, C., Tong, K., Dai, F., Zhang, Y., Zhu, W., Cheng, S., ... Liu, T. (2025). Lactate Activates the HCAR1/β-Arrestin2/PP2A Signaling Axis to Mediate STAT1/2 Dephosphorylation and Drive Osteosarcoma Progression. Advanced Science, 12(45), Article e06214. https://doi.org/10.1002/advs.202506214

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

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, lactate, osteosarcoma, STAT1/2, β-Arrestin 2",

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

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.",

year = "2025",

month = dec,

day = "4",

doi = "10.1002/advs.202506214",

language = "English",

volume = "12",

journal = "Advanced Science",

issn = "2198-3844",

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Han, Z, Jia, Q, Bai, G, Li, Z, Zeng, J, Wang, Z, Zhang, J, Cao, J, Xin, B, Liu, Y, Shen, J, Wang, L, Huang, X, Zhang, C, Tong, K, Dai, F, Zhang, Y, Zhu, W, Cheng, S, Chen, Y, Yang, X, Chen, G, Zhou, Z, Ma, Y, Liu, W, Wang, T & Liu, T 2025, 'Lactate Activates the HCAR1/β-Arrestin2/PP2A Signaling Axis to Mediate STAT1/2 Dephosphorylation and Drive Osteosarcoma Progression', Advanced Science, vol. 12, no. 45, e06214. https://doi.org/10.1002/advs.202506214

TY - JOUR

T1 - Lactate Activates the HCAR1/β-Arrestin2/PP2A Signaling Axis to Mediate STAT1/2 Dephosphorylation and Drive Osteosarcoma Progression

AU - Han, Zhitao

AU - Jia, Qi

AU - Bai, Guangjian

AU - Li, Zhao

AU - Zeng, Jin

AU - Wang, Zhenhua

AU - Zhang, Jing

AU - Cao, Jiashi

AU - Xin, Baoquan

AU - Liu, Yonggang

AU - Shen, Jingyu

AU - Wang, Lining

AU - Huang, Xing

AU - Zhang, Chunlei

AU - Tong, Kai

AU - Dai, Fenglei

AU - Zhang, Yajie

AU - Zhu, Weina

AU - Cheng, Songyi

AU - Chen, Yuanming

AU - Yang, Xinghai

AU - Chen, Guanghui

AU - Zhou, Zhenhua

AU - Ma, Yong

AU - Liu, Weibo

AU - Wang, Ting

AU - Liu, Tielong

PY - 2025/12/4

Y1 - 2025/12/4

N2 - 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.

AB - 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.

KW - HCAR1

KW - lactate

KW - osteosarcoma

KW - STAT1/2

KW - β-Arrestin 2

UR - http://www.scopus.com/inward/record.url?scp=105016327816&partnerID=8YFLogxK

U2 - 10.1002/advs.202506214

DO - 10.1002/advs.202506214

M3 - Article

AN - SCOPUS:105016327816

SN - 2198-3844

VL - 12

JO - Advanced Science

JF - Advanced Science

IS - 45

M1 - e06214

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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