Hepatic adaptation to chronic metabolic stress primes tumorigenesis

Available online 22 December 2025 In Press, Corrected Proof Article Hepatic adaptation to chronic metabolic stress primes tumorigenesis Author links open overlay panel , , , , , , , , , , , , , , , , , , , … https://doi.org/10.1016/j.cell.2025.11.031 Get rights and content Under a Creative Commons license Open access Highlights • High-fat diet (HFD) reduces hepatocyte differentiation and physiological output • Non-transformed hepatocytes activate stress and regenerative programs under HFD • These responses prime tumor formation months in the future and stratify survival • We identify regulatory roles for metabolism and intra- and intercellular signaling Summary During chronic stress, cells must support both tissue function and their own survival. Hepatocytes perform metabolic, synthetic, and detoxification roles, but chronic nutrient imbalances can induce hepatocyte death and precipitate metabolic dysfunction-associated steatohepatitis (MASH, formerly 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 that ongoing stress drives prognostic developmental and cancer-associated programs in non-transformed hepatocytes while reducing their 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. Graphical abstract Download: Download high-res image (241KB) Download: Download full-size image Keywords single-cell genomicslivermetabolismchronic stress responsetissue memoryepigenetic priminggenetic perturbationcomputational methods development 29 These authors contributed equally 30 Senior author 31 Lead contact © 2025 The Author(s). Published by Elsevier Inc.