Age-associated repression of HNF4α is a driver and potential therapeutic target in liver metabolic dysfunction

HNF4α activity is reduced in aged mouse livers despite preserved expression, linked to impaired chromatin occupancy and transcriptional activity that remodel metabolic gene regulation.

• Why it matters: Aging is a major risk factor for MASLD, but how it disrupts hepatocyte transcriptional networks to drive metabolic dysfunction is unclear. Defining HNF4’s role could reveal actionable targets to preserve liver metabolic homeostasis.
• What they did: The study profiled young versus aged mouse livers using multi-omic analyses and HNF4 CUT&RUN, then tested Hnf4a deletion or restoration with hepatocyte-specific targeted functional studies. It also used spatial transcriptomics and assessed epigenetic changes including histone acetylation, chromatin accessibility, and DNA methylation.
• The result: Aging selectively disrupted HNF4-dependent metabolic and identity programs, de-repressed inflammatory and alternative identity pathways, and altered hepatocyte zonation, consistent with lipidomic and metabolic changes. Restoring HNF4 in aged mice significantly reduced steatosis and lipid accumulation and partially reversed age-associated transcriptional changes, while inflammatory and interferon programs were not uniformly restored.

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