Dataset Summary: snRNA-seq on livers of mice overexpressing SOX4 or EGFP and fed a high-fat diet. 

Project Summary: During chronic stress, cells must support both tissue functions and their own survival. Hepatocytes perform metabolic, synthetic, and detoxification roles, but chronic nutrient imbalances can induce hepatocyte death and precipitate metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD/NASH). Despite prior work identifying stress-induced drivers of hepatocyte death, chronic stress’ functional impact on surviving cells remains unclear. Through cross-species longitudinal single-cell multi-omics, we show ongoing stress drives prognostic developmental and cancer-associated programs in non-transformed hepatocytes while reducing mature functional identity. Creating integrative computational methods, we identify and then experimentally validate master regulators perturbing hepatocyte functional balance, increasing proliferation under stress, and directly priming future tumorigenesis. Through geographic regression on human tissue microarray spatial transcriptomics, we uncover spatially-structured multicellular communities and signaling interactions shaping stress responses. Our work reveals how cells’ early solutions to chronic stress can prime future tumorigenesis and outcomes, unifying diverse modes of cellular dysfunction around core, actionable mechanisms.