PRDX6 derived from umbilical cord mesenchymal stem cells improves severe acute pancreatitis by regulating macrophage polarization via inhibiting the ROS/P65/IRF7 axis.

Aberrant polarization of macrophages drives the inflammatory cascade in severe acute pancreatitis (SAP), while umbilical cord mesenchymal stem cells (UCMSCs) exhibit therapeutic potential through immunoregulation. This study demonstrated that peroxiredoxin 6 (PRDX6), a secretory protein derived from UCMSCs, reduces the level of reactive oxygen species (ROS) in macrophages, inhibits the phosphorylation of P65 and IRF7, and blocks the type I interferon signaling pathway. Consequently, it drives the polarization of macrophages from the pro-inflammatory phenotype (M1) to the anti-inflammatory phenotype (M2), significantly alleviating multi-organ damage and inflammatory responses in SAP mice. Mechanistic validation showed that macrophage-specific overexpression of interferon regulatory factor 7 (IRF7) mediated by the AAV9 lentiviral vector could antagonize this effect, whereas silencing PRDX6 in UCMSCs weakened their therapeutic role. Based on these findings, we developed engineered UCMSCs with PRDX6 overexpression and constructed macrophage-targeted F4/80-EVs by modifying their secreted extracellular vesicles (EVs) with F4/80 antibodies. Compared with natural EVs, F4/80-EVs significantly enhanced the ability to regulate macrophage polarization and the therapeutic effect on SAP. This study reveals the mechanism by which the UCMSCs-PRDX6 axis reprograms macrophage polarization through the ROS/p65/IRF7 pathway for the treatment of SAP, and establishes a targeted delivery system with potential for clinical translation.