Dysregulated m 6 A via compensatory arginine methylation primes premalignancy in metabolic dysfunction–associated steatotic liver disease

Hepatocellular carcinoma (HCC) originates from premalignant disease-associated hepatocytes (daHeps) that emerge during the progression of metabolic dysfunction–associated steatotic liver disease (MASLD) to metabolic dysfunction–associated steatohepatitis (MASH). As daHeps are compensatorily primed by metabolic stress, we reproduced the accelerated progression of MASLD-associated HCC in mice by phenocopying the decreased expression of a metabolic regulator, protein arginine methyltransferase 1 (PRMT1). In Prmt1 liver-specific knockout (LKO), m 6 A-mediated changes in mRNA stability reprogram the transcriptome via paralog compensation; increased PRMT6 activates m 6 A methyltransferases by inducing asymmetric arginine dimethylation of METTL3. This event enhances global m 6 A deposition that leads to the down-regulation of Keap1 , which would trigger the NRF2 axis, promoting premalignancy; under diet- and chemical-induced stress, the incidence of steatohepatitic HCC was increased, clinically correlating with the PRMT-METTL3-NRF2 pathway. Together, we propose that compensatory arginine methylation primes MASLD-associated HCC by modulating m 6 A-mediated transcriptome and NRF2 regulatory pathways as adaptive defenses against metabolic and oxidative stress.