Methionine and choline deficiency rewires transcriptional programs to recapitulate molecular features of human MASH

Across cell types, lack of methionine and choline induced transcriptional program of inflammatory and stress response and suppressed metabolic pathways and cell-cycle progression, suggesting a proliferation pause as a compensatory stress-adaptive response that preserves cell viability and essential functions. In addition to these shared responses, MCD stress also caused distinct cell type-specific outputs that could contribute to the pathogenesis of MASH.

Integrated analysis of these datasets with human MASH liver single nucleus transcriptomic data demonstrated that MCD condition recapitulates multiple pathophysiological features of human MASH, including the elevated inflammation, enhanced hepatocyte death, disrupted redox balance, altered metabolic homeostasis, and HSC activation. These findings not only uncover how MCD stress promotes MASH progression, but also provide a conceptual basis to guide future use of MCD diet-induced models in MASH studies.