小鼠急性肝损伤早期，中间带肝细胞经 Atf4-Chop 轴以增殖换生存
Mid-zone hepatocytes trade proliferation for survival via Atf4-Chop axis in early acute liver injury
在小鼠对乙酰氨基酚（APAP）诱导的急性肝损伤模型中，肝细胞出现短暂增殖抑制，以中间带肝细胞最明显，与 APAP 代谢的区域分布一致。空间转录组（ST）分析识别出以 Atf4-Chop 轴为核心的中间带特异应激反应程序，Cut&Run 结合免疫组化与功能实验显示该轴通过细胞周期抑制因子 Btg2 抑制增殖。中间带肝细胞因此短暂优先应激适应而非增殖，从而为后续肝修复保留再生能力。
来源：eLife · doi.org
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.