Background <p>Ischemia–reperfusion (I/R) injury frequently arises during liver surgery and significantly contributes to postoperative liver failure and graft dysfunction. Macrophage-mediated pyroptosis cascade plays a crucial effect in liver I/R injury. The attribution of pyroptosis in macrophage reprogramming and hepatic microenvironment during liver I/R remain unclear. Here, we identify <i>AXL</i> as a hepatic macrophage-enriched gene that regulates pyroptosis in I/R injury.</p> Methods <p>We collected liver grafts to test the relationship between phosphorylated AXL (p-AXL) and degree of hepatic injury. We isolated primary mouse hepatocytes and macrophages for hypoxia/reoxygenation (H/R) treatment and coculture, and used macrophage depletion mice to reveal the unique function of AXL in hepatic macrophages. Mice were treated with activators and inhibitors of AXL, NLRP3, and XBP1, and subjected to liver I/R to determine the mechanism underlying AXL-mediated modulation of the hepatic microenvironment.</p> Results <p>We found that AXL inhibition and NLRP3-induced pyroptosis was strongly associated with the degree of liver I/R injury. Further analysis revealed that AXL activation in macrophages suppressed hepatic I/R-induced pyroptosis. AXL activation with Gas6, a high-affinity ligand for AXL, significantly attenuated liver I/R injury and improved the hepatic microenvironment. Mechanistically, AXL activation impeded the IRE1–XBP1s axis to suppress NLRP3 inflammasome activation, which promoted hepatic macrophages to an alternative-like polarization, thereby enhancing the hepatic immune environment to attenuate liver I/R injury.</p> Conclusions <p>This study not only elucidates how AXL reprograms macrophages but also suggests a therapeutic target for mitigating liver I/R injury.</p> Graphical abstract <p></p>