Impeding two p53-pathways fosters HCC initiation via MTHFD1L-RNA m6A-elicited autonomous cell growth and immune evasion

We demonstrated that carcinogen- or unhealthy diet-induced HCC initiation is accelerated in DKI mice, and the p53- pathways are activated in human cirrhotic livers. We futher identified a one-carbon metabolism (1CM) enzyme methylenetetrahydrofolate dehydrogenase 1 like (MTHFD1L) as the p53-suppressed player in HCC initiation. MTHFD1L promotes HCC initiation by enhancing autonomous cell growth and immune evasion of HCC progenitor cells (HcPCs).

With Nanopore RNA sequencing, we unveiled that MTHFD1L fulfills these bi-functions by fueling methionine cycle that produces methyl groups to maintain mRNA m6A of cell growth mediators Prickle1 and Snail, and B2m, a light chain of MHC-I critical for antigen presentation. Conclusions: Stress-MDM2/MDMX-p53-MTHFD1L-RNA m6A pathways are crucial for preventing HCC initiation by reversing 1CM reprogramming-boosted cell autonomous growth and immune evasion.