Dysregulated m⁶A via compensatory arginine methylation primes premalignancy in metabolic dysfunction-associated...

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), m⁶A-mediated changes in mRNA stability reprogram the transcriptome via paralog compensation; increased PRMT6 activates m⁶A methyltransferases by inducing asymmetric arginine dimethylation of METTL3. This event enhances global m⁶A 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 m⁶A-mediated transcriptome and NRF2 regulatory pathways as adaptive defenses against metabolic and oxidative stress.