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  3. Lysophosphatidylethanolamine 18:1 drives clear cell renal cell carcinoma by stabilizing SIRT6 to reprogram lipid metabolism

Lysophosphatidylethanolamine 18:1 drives clear cell renal cell carcinoma by stabilizing SIRT6 to reprogram lipid metabolism

  • Signal Transduct Target Ther. 2025 Dec 8;10(1):398. doi: 10.1038/s41392-025-02496-1.
Nanxi Yue # 1,  Hongye Zhao # 1,  Yong Zhang # 2,  Junfei Gu # 3,  Jinchun Qi 3,  Jinkun Wen 1,  Wei Wang 1,  Mingming Lv 1,  Hao Sun 1,  Jinsuo Chen 4,  Chenxiao Yang 5,  Changbao Qu 6,  Xiaonan Chen 7,  Zhan Yang 8 9
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, Hebei, PR China.
  • 2 Department of Urology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 3 Department of Urology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
  • 4 School of Clinical Medicine, Hebei University, Department of Urology, Affiliated Hospital of Hebei University, Baoding, China.
  • 5 Center of Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
  • 6 Department of Urology, Shijiazhuang People's Hospital, Shijiazhuang, Hebei, China. changbao_qu@126.com.
  • 7 Department of Urology, Shengjing Hospital of China Medical University, Shenyang, PR China. chenxn@cmu.edu.cn.
  • 8 Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, Hebei, PR China. yangzhan@hebmu.edu.cn.
  • 9 Center of Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China. yangzhan@hebmu.edu.cn.
  • # Contributed equally.
PMID: 41354870 DOI: 10.1038/s41392-025-02496-1
Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by profound lipid metabolic dysregulation, yet the mechanisms linking peritumoral adipose tissue (PAT)-derived lipid metabolites to tumor aggressiveness remain poorly defined. Here, we identified lysophosphatidylethanolamine 18:1 (LPE18:1), a lipid metabolite enriched in PAT and the arterial blood of ccRCC patients, as a critical driver of tumor growth and lipid deposition. Through multiomics analyses and functional studies, we demonstrated that LPE18:1 upregulates F-actin-capping protein subunit alpha-1 (CAPZA1), which recruits ubiquitin-specific peptidase 48 (USP48) to stabilize the NAD-dependent protein deacetylase sirtuin-6 (SIRT6) by inhibiting its proteasomal degradation. Increased SIRT6 epigenetically promotes acetyl-CoA acetyltransferase 2 (ACAT2) expression, redirecting lipid metabolism toward free Cholesterol accumulation-a hallmark of ccRCC aggressiveness. Clinically, CAPZA1 and SIRT6 levels correlate with advanced tumor stage and poor prognosis in ccRCC cohorts. Genetic or pharmacological inhibition of the CAPZA1/SIRT6 axis can reverse LPE18:1-induced lipid deposition and tumor progression in xenograft models. Notably, targeting this axis with the SIRT6 Inhibitor OSS-128167 combined with CAPZA1 depletion significantly suppresses ccRCC cell growth. Our study reveals a PAT-derived lipid metabolite-fuelled signaling cascade that reprograms lipid metabolism in ccRCC, identifying CAPZA1/USP48/SIRT6 as actionable therapeutic targets for metabolic malignancies.

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