Cps1, or carbamoyl phosphate synthetase-1, is the first and rate-limiting enzyme of the urea cycle in mammals. It is responsible for converting toxic ammonia into non-toxic urea by producing carbamoyl phosphate from ammonia and bicarbonate in the mitochondria, thus playing a crucial role in nitrogen disposal [2,3]. Disruptions in Cps1 function can lead to elevated ammonia levels and neurological injury [2]. Additionally, it is involved in other metabolic processes such as pyrimidine metabolism [1].

In KRAS/LKB1-mutant non-small-cell lung cancer (NSCLC) cells, LKB1 suppresses Cps1 transcription through AMPK. Silencing Cps1 in these cells induces cell death due to pyrimidine depletion, reducing tumour growth, as Cps1 enables an unconventional nitrogen flow pathway into pyrimidines [1]. In drug-induced liver failure caused by acetaminophen (APAP) overdose, APAP exposure leads to Cps1 deISGylation and degradation, resulting in ammonia clearance dysfunction. Knockout of GSDME, which promotes Cps1 deISGylation, protects mice from APAP-DILI [4].

In conclusion, Cps1 is essential for ammonia detoxification via the urea cycle and has a significant impact on metabolic processes like pyrimidine synthesis. Model-based research, such as gene knockout studies in mice, has revealed its role in diseases including NSCLC and drug-induced liver failure, enhancing our understanding of disease mechanisms and potentially guiding therapeutic strategies.