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 and Qing Zhang ()
Additional contact information
Chengheng Liao: University of Texas Southwestern Medical Center
Lianxin Hu: University of Texas Southwestern Medical Center
Liwei Jia: University of Texas Southwestern Medical Center
Jin Zhou: University of Texas Southwestern Medical Center
Tao Wang: University of Texas Southwestern Medical Center
Kangsan Kim: University of Texas Southwestern Medical Center
Hua Zhong: University of Texas Southwestern Medical Center
Hongwei Yao: University of Texas Southwestern Medical Center
Lei Dong: University of Texas Southwestern Medical Center
Lei Guo: University of Texas Southwestern Medical Center
Qian Liang: University of Texas Southwestern Medical Center
Cheng Zhang: University of Texas Southwestern Medical Center
Fangzhou Zhao: University of Texas Southwestern Medical Center
Jun Fang: University of Texas Southwestern Medical Center
Hongyi Liu: University of Texas Southwestern Medical Center
Shina Li: University of Texas Southwestern Medical Center
Lin Xu: University of Texas Southwestern Medical Center
Jeremy M. Simon: Dana-Farber Cancer Institute
Srinivas Malladi: University of Texas Southwestern Medical Center
Payal Kapur: University of Texas Southwestern Medical Center
James Brugarolas: University of Texas Southwestern Medical Center
Ralph J. DeBerardinis: University of Texas Southwestern Medical Center
Qing Zhang: University of Texas Southwestern Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56955-y

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