Female-specific m6A remodeling in the liver correlates with post-transcriptional metabolic adaptation to high fat diet

To examine sex-specific hepatic adaptation to high-fat (HF) diet mouse model of MASLD, we integrated proteomics, transcriptomics, and Oxford Nanopore direct RNA sequencing for transcriptome-wide m6A profiling in male and female mouse livers.

Female mice were relatively protected from HF diet–induced hepatic steatosis and exhibited distinct proteome remodeling enriched for peroxisomal pathways. In contrast, transcriptomic responses in females were dominated by inflammatory signatures and did not recapitulate the metabolic adaptations observed at the protein level, revealing extensive RNA–protein discordance and post-transcriptional remodeling. Integrated RNA–protein analyses identified female-specific amplification of peroxisomal proteins despite modest transcript-level changes.