The impact of p53 on the urea cycle and nitrogen metabolism enzymes: Mechanisms and implications for cancer development

Abstract

The tumour suppressor protein p53, encoded by the TP53 gene, is widely celebrated as the “guardian of the genome,” yet its role in metabolic reprogramming, particularly nitrogen metabolism, remains underappreciated. This review highlights the emerging nexus between p53 and the urea cycle, a key pathway responsible for ammonia detoxification and the generation of biosynthetic precursors. By regulating the expression and activity of urea cycle enzymes, p53 exerts profound control over interconnected metabolic pathways, including the metabolism of polyamine, methionine, glutathione, and proline. Cancer cells, with their voracious nitrogen demand, co-opt urea cycle dysregulation to fuel tumour growth and survival. Here, we synthesise the latest insights into p53's role in nitrogen homeostasis, delineating its broader implications for cellular metabolism and carcinogenesis. Additionally, we propose the strategic targeting of urea cycle enzymes as novel prognostic biomarkers and therapeutic vulnerabilities in cancer. This work not only redefines the metabolic scope of p53 but also positions nitrogen metabolism at the forefront of cancer research, offering transformative avenues for therapeutic innovation.