USF1 promotes urea cycle dysregulation and migration of ccRCC through inhibiting ASS1

Renal clear cell carcinoma (ccRCC) is a prevalent kidney cancer characterized by its metabolic reprogramming and metastatic potential. Understanding the molecular pathways contributing to abnormal metabolism and metastasis in ccRCC is crucial. In this study, we have identified the downregulation of rate-limiting enzyme argininosuccinate synthase 1 (ASS1), the rate-limiting enzyme of urea cycle, and successfully demonstrated the presence of urea cycle dysfunction (UCD) regulated by ASS1 in ccRCC. To elucidate the downregulation of ASS1 in ccRCC, we predicted the transcription factors that bind to the ASS1 promoter and identified USF1 as a highly expressed factor in ccRCC tissues, which is associated with poor prognosis. USF1 plays a pivotal role in promoting UCD of ccRCC through inhibiting ASS1 transcription. Notably, USF1 enhances migration and invasion of ccRCC cells both in vivo and in vitro. Collectively, these insights provide implications for understanding ccRCC progression and uncovers a regulatory axis involving overexpression of USF1 leading to downregulation of ASS1.