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  3. Metabolic profiling reveals pyrimidine synthesis enzyme CAD as a central carbon metabolism signaling node in cancer cell proliferation

Metabolic profiling reveals pyrimidine synthesis enzyme CAD as a central carbon metabolism signaling node in cancer cell proliferation

  • Mol Cell. 2026 Apr 16;86(8):1529-1545.e7. doi: 10.1016/j.molcel.2026.03.016.
Chao Qin 1,  Zhenhao An 1,  Shu Feng 2,  Wen Fu 1,  Xinchi Xie 1,  Ali Can Savas 1,  Taolin Xie 1,  Charles Brenner 3,  Takeshi Saito 4,  Pinghui Feng 5
Affiliations

Affiliations

  • 1 Section of Infection and Immunity, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90089, USA.
  • 2 Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA; Department of Microbial Health Sciences and Center for Global Pathogen Infection, Cleveland Clinic Research, Cleveland, OH, USA.
  • 3 Department of Diabetes and Cancer Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • 4 Division of Gastrointestinal and Liver Diseases, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, USA; Department of Pathology, University of Southern California, Los Angeles, CA 90033, USA; Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
  • 5 Section of Infection and Immunity, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90089, USA; Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA; Department of Microbial Health Sciences and Center for Global Pathogen Infection, Center for Experimental Therapeutics, Cleveland, OH, USA. Electronic address: [email protected].
PMID: 41950920 DOI: 10.1016/j.molcel.2026.03.016
Abstract

Rapid Cancer cell proliferation requires extensive macromolecular biosynthesis, yet how distinct anabolic pathways are coordinated remains incompletely understood. Here, we report that the trifunctional carbamoyl-phosphate synthase, aspartate transcarbamoylase, and dihydroorotase (CAD) activates key glycolytic Enzymes to support biosynthesis and Cancer cell proliferation. When Cancer proteomics datasets were queried, a CAD activation signature was identified in diverse tumors. Metabolomics analysis revealed that CAD fuels central carbon metabolism, specifically the pentose phosphate pathway (PPP) and serine synthesis pathway (SSP). Mechanistically, CAD deamidates and activates glucose-6-phosphate dehydrogenase (G6PD) and phosphoglycerate dehydrogenase (PHGDH), rate-limiting Enzymes of the PPP and SSP, respectively, which are fully recapitulated by the Glutaminase domain of CAD. Functional interrogation of cancer-associated CAD mutations and human hepatocellular carcinoma tumors predicts the metabolic signature endowed by G6PD and PHGDH deamidation. Simultaneous inhibition of G6PD and PHGDH effectively impeded tumor formation. This work identifies CAD as a central carbon metabolism signaling node and a potential therapeutic target.

Keywords

CAD; Cancer metabolism; G6PD; PHGDH; central carbon metabolism; deamidation; pyrimidine synthesis; the pentose phosphate pathway; the serine synthesis pathway.

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