RNASET2 Deficiency Induces Hepatocellular Carcinoma Metastasis through Cholesterol‐Triggered MET Activation

Abstract Metastasis remains a significant challenge in the treatment of hepatocellular carcinoma (HCC). The role of ribonuclease T2 (RNASET2) in HCC is still uncertain, although it has been reported to have contradictory effects on some cancers. Here, it is demonstrated that RNASET2 knockout leads to significant accumulation of cholesterol, which in turn promotes MET‐mediated HCC metastasis. Mechanistically, the absence of RNASET2 hinders the degradation of RNA into uridine, thereby reducing the conversion to UTP. This reduction restrains glucuronate metabolism and the expression of the related enzyme UDP‐glucuronosyltransferase (UGT)1A1, ultimately resulting in the accumulation of cholesterol due to decreased formation of glucuronidated‐bile acids. The administration of cholesterol induces the migration and invasion of HCC cells through MET (mesenchymal‐epithelial transition factor) activation. However, the deficiency of RNASET2‐induced HCC metastasis can be reversed by blocking MET with shRNA or savolitinib. The study identifies RNASET2 as a key regulator that coordinates RNA, glucuronate, and cholesterol metabolism. Its deficiency drives HCC metastasis through cholesterol‐triggered MET activation. These findings highlight the potential of targeting RNASET2 and MET in improving the prognosis of HCC.