Blocking MET activation reverses RNASET2 deficiency-induced HCC metastasis driven by cholesterol accumulation

Ribonuclease T2 (RNASET2), the only member of the human RNase T2 family, plays important roles in RNA cleavage. While its involvement in several cancers is known, its functions in HCC (hepatocellular carcinoma) remain unclear. In this study, we reveal that RNASET2 deficiency leads to cholesterol accumulation, MET signaling activation, and HCC metastasis aggravation. Interestingly, the deficiency of RNASET2 results in diminished degradation of RNA into uridine, which in turn suppresses glucuronate metabolism and reduces the levels of UDP-glucuronosyltransferase (UGT)1A1, a crucial enzyme involved in bile acids, hormone, and drug biotransformation. This impaired cholesterol elimination through bile acids. Our findings demonstrate that RNASET2 plays a role in converging RNA, glucuronate, and cholesterol metabolism to trigger MET activation. This study contributes to our understanding of RNA degradation and provides insights into tumor metabolism reprogramming.