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

Hepatocytes undergo extensive proliferation to facilitate liver repair after injury, yet early adaptive changes prior to proliferation remain unclear. Using a mouse model of acetaminophen (APAP)-induced liver injury, we show that hepatocytes undergo transient proliferation suppression that is most pronounced in mid-zone hepatocytes, consistent with zonal APAP metabolism. Although spatial transcriptomics (ST) alone could not independently confirm zonal proliferative restraint, ST analysis identified a unique mid-zone stress-response program centered on the Atf4-Chop axis. By integrating Cut&Run with immunohistochemistry and functional studies, we found that the Atf4-Chop axis 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.