Mid-zone hepatocytes trade proliferation for survival via Atf4-Chop axis in early acute liver injury

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Hepatocytes undergo extensive proliferation to facilitate liver repair after injury, yet early adaptive changes prior to proliferation remain unclear. Here, we report that during early acetaminophen (APAP)-induced liver injury, hepatocytes exhibit transient proliferation suppression that is most pronounced in mid-zone hepatocytes, consistent with zonal APAP metabolism. While spatial transcriptomics (ST) provided robust evidence for this arrest in the mid-zone, support for a similar arrest in pericentral hepatocytes was limited. Integrating ST with immunohistochemistry and functional studies, we identified a unique mid-zone stress-response program centered on the Atf4–Chop axis, which suppresses proliferation via the cell cycle inhibitor Btg2. Together, our findings support a model in which mid-zone hepatocytes transiently prioritize stress adaptation over proliferation, thereby preserving regenerative capacity for subsequent liver repair.

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