PTX3 aggravates ischemia-reperfusion injury in steatotic liver by promoting M1 macrophage polarization via activation of the JAK1/STAT1 pathway.

The heightened susceptibility of fatty liver grafts to ischemia-reperfusion injury (IRI) constitutes a major challenge in clinical liver transplantation, where macrophage-mediated inflammation is a key driver. However, the specific regulatory mechanisms within the fatty liver microenvironment remain unclear. Therefore, this study aimed to investigate the role of Pentraxin 3 (PTX3) in macrophage polarization during fatty liver IRI and to elucidate its underlying molecular mechanism. Using a high-fat diet-induced murine fatty liver IRI model together with a hypoxia/reoxygenation co-culture system of hepatocytes and macrophages, we found that PTX3 expression was markedly increased during fatty liver IRI. Macrophage-specific overexpression of PTX3 further aggravated liver injury, accompanied by enhanced M1 macrophage polarization, increased production of pro-inflammatory cytokines, and aggravated hepatocyte apoptosis. In vitro, PTX3 similarly promoted M1 macrophage polarization and inflammatory responses under hypoxia/reoxygenation conditions. Mechanistically, PTX3 promoted M1 macrophage polarization through activation of the JAK1/STAT1 signaling pathway, whereas treatment with the JAK1/2 inhibitor ruxolitinib effectively blocked PTX3-induced M1 macrophage polarization and alleviated inflammatory injury. These findings suggest that the PTX3/JAK1/STAT1 signaling axis links the fatty liver microenvironment to macrophage-driven inflammation and may represent a potential therapeutic target for fatty liver graft transplantation.