BBOX1 restrains TBK1-mTORC1 oncogenic signaling in clear cell renal cell carcinoma

Chengheng Liao; Lianxin Hu; Liwei Jia; Jin Zhou; Tao Wang; Kangsan Kim; Hua Zhong; Hongwei Yao; Lei Dong; Lei Guo; Qian Liang; Cheng Zhang; Fangzhou Zhao; Jun Fang; Hongyi Liu; Shina Li; Lin Xu; Jeremy M. Simon; Srinivas Malladi; Payal Kapur; James Brugarolas; Ralph J. DeBerardinis; Qing Zhang

doi:10.1038/s41467-025-56955-y

BBOX1 restrains TBK1-mTORC1 oncogenic signaling in clear cell renal cell carcinoma

Chengheng Liao, Lianxin Hu, Liwei Jia, Jin Zhou, Tao Wang, Kangsan Kim, Hua Zhong, Hongwei Yao, Lei Dong, Lei Guo, Qian Liang, Cheng Zhang, Fangzhou Zhao, Jun Fang, Hongyi Liu, Shina Li, Lin Xu, Jeremy M. Simon, Srinivas Malladi, Payal KapurJames Brugarolas, Ralph J. DeBerardinis, Qing Zhang

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

2 Scopus citations

Abstract

Clear cell renal cell carcinoma (ccRCC), a metabolic disease originating from renal proximal convoluted tubule (PCT) epithelial cells, remains incompletely understood in terms of its initiating signaling events. Here, we identify γ-butyrobetaine hydroxylase 1 (BBOX1), a key enzyme in carnitine synthesis predominantly expressed in PCT cells, as a tumor suppressor in ccRCC. BBOX1 expression is lost during ccRCC malignant transformation, and its restoration reduces cell viability in physiological medium and inhibits xenograft tumor growth. Transcriptomic analyses reveal that BBOX1 suppresses critical metabolic pathways including mTORC1 signaling and glycolysis in ccRCC. Further, we identify TANK-binding kinase 1 (TBK1) as an essential mediator of mTORC1 and glycolysis activation and as a target of BBOX1-mediated tumor suppression. Mechanistically, BBOX1 disrupts TBK1 activation by preventing its interaction with the upstream activator doublecortin-like kinase 2 (DCLK2). This BBOX1-DCLK2-TBK1 axis unveils an important mechanism in ccRCC metabolic dysregulation and highlights potential therapeutic strategies.

Original language	English (US)
Article number	1543
Journal	Nature communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-56955-y
State	Published - Dec 2025

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Liao, C., Hu, L., Jia, L., Zhou, J., Wang, T., Kim, K., Zhong, H., Yao, H., Dong, L., Guo, L., Liang, Q., Zhang, C., Zhao, F., Fang, J., Liu, H., Li, S., Xu, L., Simon, J. M., Malladi, S., ... Zhang, Q. (2025). BBOX1 restrains TBK1-mTORC1 oncogenic signaling in clear cell renal cell carcinoma. Nature communications, 16(1), Article 1543. https://doi.org/10.1038/s41467-025-56955-y

Liao, C, Hu, L, Jia, L, Zhou, J, Wang, T, Kim, K, Zhong, H, Yao, H, Dong, L, Guo, L, Liang, Q, Zhang, C, Zhao, F, Fang, J, Liu, H, Li, S, Xu, L, Simon, JM, Malladi, S , Kapur, P , Brugarolas, J , DeBerardinis, RJ & Zhang, Q 2025, 'BBOX1 restrains TBK1-mTORC1 oncogenic signaling in clear cell renal cell carcinoma', Nature communications, vol. 16, no. 1, 1543. https://doi.org/10.1038/s41467-025-56955-y

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title = "BBOX1 restrains TBK1-mTORC1 oncogenic signaling in clear cell renal cell carcinoma",

abstract = "Clear cell renal cell carcinoma (ccRCC), a metabolic disease originating from renal proximal convoluted tubule (PCT) epithelial cells, remains incompletely understood in terms of its initiating signaling events. Here, we identify γ-butyrobetaine hydroxylase 1 (BBOX1), a key enzyme in carnitine synthesis predominantly expressed in PCT cells, as a tumor suppressor in ccRCC. BBOX1 expression is lost during ccRCC malignant transformation, and its restoration reduces cell viability in physiological medium and inhibits xenograft tumor growth. Transcriptomic analyses reveal that BBOX1 suppresses critical metabolic pathways including mTORC1 signaling and glycolysis in ccRCC. Further, we identify TANK-binding kinase 1 (TBK1) as an essential mediator of mTORC1 and glycolysis activation and as a target of BBOX1-mediated tumor suppression. Mechanistically, BBOX1 disrupts TBK1 activation by preventing its interaction with the upstream activator doublecortin-like kinase 2 (DCLK2). This BBOX1-DCLK2-TBK1 axis unveils an important mechanism in ccRCC metabolic dysregulation and highlights potential therapeutic strategies.",

author = "Chengheng Liao and Lianxin Hu and Liwei Jia and Jin Zhou and Tao Wang and Kangsan Kim and Hua Zhong and Hongwei Yao and Lei Dong and Lei Guo and Qian Liang and Cheng Zhang and Fangzhou Zhao and Jun Fang and Hongyi Liu and Shina Li and Lin Xu and Simon, {Jeremy M.} and Srinivas Malladi and Payal Kapur and James Brugarolas and DeBerardinis, {Ralph J.} and Qing Zhang",

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AU - Liao, Chengheng

AU - Hu, Lianxin

AU - Jia, Liwei

AU - Zhou, Jin

AU - Wang, Tao

AU - Kim, Kangsan

AU - Zhong, Hua

AU - Yao, Hongwei

AU - Dong, Lei

AU - Guo, Lei

AU - Liang, Qian

AU - Zhang, Cheng

AU - Zhao, Fangzhou

AU - Fang, Jun

AU - Liu, Hongyi

AU - Li, Shina

AU - Xu, Lin

AU - Simon, Jeremy M.

AU - Malladi, Srinivas

AU - Kapur, Payal

AU - Brugarolas, James

AU - DeBerardinis, Ralph J.

AU - Zhang, Qing

PY - 2025/12

Y1 - 2025/12

N2 - Clear cell renal cell carcinoma (ccRCC), a metabolic disease originating from renal proximal convoluted tubule (PCT) epithelial cells, remains incompletely understood in terms of its initiating signaling events. Here, we identify γ-butyrobetaine hydroxylase 1 (BBOX1), a key enzyme in carnitine synthesis predominantly expressed in PCT cells, as a tumor suppressor in ccRCC. BBOX1 expression is lost during ccRCC malignant transformation, and its restoration reduces cell viability in physiological medium and inhibits xenograft tumor growth. Transcriptomic analyses reveal that BBOX1 suppresses critical metabolic pathways including mTORC1 signaling and glycolysis in ccRCC. Further, we identify TANK-binding kinase 1 (TBK1) as an essential mediator of mTORC1 and glycolysis activation and as a target of BBOX1-mediated tumor suppression. Mechanistically, BBOX1 disrupts TBK1 activation by preventing its interaction with the upstream activator doublecortin-like kinase 2 (DCLK2). This BBOX1-DCLK2-TBK1 axis unveils an important mechanism in ccRCC metabolic dysregulation and highlights potential therapeutic strategies.

AB - Clear cell renal cell carcinoma (ccRCC), a metabolic disease originating from renal proximal convoluted tubule (PCT) epithelial cells, remains incompletely understood in terms of its initiating signaling events. Here, we identify γ-butyrobetaine hydroxylase 1 (BBOX1), a key enzyme in carnitine synthesis predominantly expressed in PCT cells, as a tumor suppressor in ccRCC. BBOX1 expression is lost during ccRCC malignant transformation, and its restoration reduces cell viability in physiological medium and inhibits xenograft tumor growth. Transcriptomic analyses reveal that BBOX1 suppresses critical metabolic pathways including mTORC1 signaling and glycolysis in ccRCC. Further, we identify TANK-binding kinase 1 (TBK1) as an essential mediator of mTORC1 and glycolysis activation and as a target of BBOX1-mediated tumor suppression. Mechanistically, BBOX1 disrupts TBK1 activation by preventing its interaction with the upstream activator doublecortin-like kinase 2 (DCLK2). This BBOX1-DCLK2-TBK1 axis unveils an important mechanism in ccRCC metabolic dysregulation and highlights potential therapeutic strategies.

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BBOX1 restrains TBK1-mTORC1 oncogenic signaling in clear cell renal cell carcinoma

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