IRP1 affects the long-term survival and function of iTregs by regulating ferroptosis and apoptosis.

As an important classification of Tregs, iTregs play a critical role in inducing transplant immune tolerance. Iron metabolism is closely linked to iTreg function, and IRP1 serves as a central regulator of cellular iron homeostasis. However, the relationship between IRP1 and iTreg ferroptosis remains unclear. In this study, RNA-seq analysis identified ferroptosis as one of the major pathways altered by IRP1 knockdown in iTregs. Subsequent experiments showed reduced ROS accumulation and lipid peroxidation, together with increased GSH levels and GPX4 expression, indicating attenuated ferroptotic stress. Concurrently, diminished CHAC1 expression attenuated its pro-apoptotic cascade signaling, leading to decreased apoptosis. Fer-1, a synthetic small molecule compound, was used to demonstrate that the suppression of both ferroptosis and apoptosis enhanced iTreg long-term survival and reinforced their immunosuppressive function. In an xeno-GvHD model, IRP1-knockdown iTregs outperformed normal iTregs in mitigating rejection responses, thereby promoting transplant immune homeostasis. This study might provide good inspiration for improving the therapeutic efficacy of organ transplantation.