Impaired nitrogenous waste clearance promotes hepatocellular carcinoma
In mammals, hepatic urea cycle enzymes (UCEs) convert ammonia, the toxic nitrogenous waste, into urea for excretion. In hepatocellular carcinoma (HCC), UCE expression is often heterogeneously repressed, but its role in tumorigenesis is unclear. We show that, as in patients, UCE expression is markedly reduced in multiple HCC mouse models, including those driven by oncogenic c-MET/β-catenin, leading to impaired ammonia clearance, altered amino acid metabolism, and increased pyrimidine synthesis. In contrast, UCE expression is largely preserved in c-MET/sgAxin1 tumors, allowing assessment of the consequences of UCE loss. Silencing individual UCEs increases ammonia burden and accelerates HCC with reprogrammed amino acid and pyrimidine metabolism, supporting a causal role for defective ammonia detoxification in oncogenesis. Notably, dietary protein restriction lowers hepatic ammonia and slows tumor growth. These findings establish a mechanistic link between nitrogen overload and hepatocarcinogenesis and highlight protein restriction as a feasible therapeutic strategy for patients with impaired nitrogenous waste handling.
Authors
- Wei-Xing zong
- Richard Z. Lin (ORCID: https://orcid.org/0000-0002-3967-0859)
- ShengLan Gao
- Heineken Queen (ORCID: https://orcid.org/0000-0002-3669-1144)
- Jianliang Shen (ORCID: https://orcid.org/0009-0008-5474-7405)
- Qingqing Mao (ORCID: https://orcid.org/0009-0000-5495-0608)
- Junrong Yan (ORCID: https://orcid.org/0000-0002-4017-6065)
- Jiekun Yang (ORCID: https://orcid.org/0000-0003-0920-052X)
- Tracy G. Anthony (ORCID: https://orcid.org/0000-0002-8586-5884)
- Hong Li (ORCID: https://orcid.org/0000-0001-8591-4167)
- Xin Chen (ORCID: https://orcid.org/0000-0002-4041-9960)
- Weiwei Dai
- Rahul Tacke
- Xinlu Han
- Tong Liu
- Ping Xie
- M. Celeste Simon
- Xiaoyang Su
- Mark C. Koch
- Ariful Islam
Institutions
- Rutgers, The State University of New Jersey (US)
- University of Hawaiʻi at Mānoa (US)
- University of Hawaii System (US)
- Fudan University (CN)
- Cancer Center of Hawaii (US)
- University Medical Center of Princeton (US)
- Northport VA Medical Center (US)
- University of Hawaii Cancer Center
- Stony Brook University (US)
- Xi’an Jiaotong-Liverpool University (CN)
- University of Pennsylvania (US)
Publication Details
- Journal
- Science Advances
- Published
- 2026-01-09
- DOI
- https://doi.org/10.1126/sciadv.aec0766
- Citations
- 1
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 24.82