Chromatin Remodeling in Pericentral Hepatocytes Modulates MASH via CYP450 Activity

Lgr5+ hepatocytes constitute a specialized lineage central to nutrient and xenobiotic metabolism. In chronic metabolic liver diseases such as MASLD and MASH, lipid accumulation occurs throughout the liver, yet the zone-specific hepatocyte response to metabolic stress remains poorly understood.

Using multi-omics and lineage-specific knockout models, we show that DPF2, a SWI/SNF subunit in Lgr5+ hepatocytes, is essential for maintaining hepatic metabolic homeostasis. Loss of Dpf2 in these cells drives severe MASLD by upregulating CYP2 enzymes, which excessively metabolize all-trans retinoic acid (atRA).