Fig 1: MG53 interacts with MPEG1 to regulate MVP–STAT6 signaling and promote macrophage M2 polarization. (A) Membrane Proteome Array (MPA) screening identified MPEG1 as one of the top binding candidates for MG53, along with PCDHGA6 and PCDH17. (B) Co‐immunoprecipitation showing the interaction between Flag‐tagged human MPEG1 and mCherry‐MG53 in HEK293T cells. (C) Western blot analysis of cytoplasmic and nuclear fractions in HEK293T cells overexpressing Flag‐hMPEG1 and treated with recombinant human MG53 (rhMG53, 40 ng/mL). Overexpression of MPEG1 facilitated cellular entry of exogenous MG53, as detected in both cytoplasmic and nuclear fractions. Lamin A/C and GAPDH served as nuclear and cytoplasmic markers, respectively. (D) Western blot analysis of IL‐4–induced signaling in BMDMs treated with different doses of rhMG53. MG53 enhanced IL‐4–induced STAT6 phosphorylation. (E) Quantification of p‐STAT6 levels normalized to total protein expression. Data are presented as mean ± SD from three independent experiments. * p < 0.05. (F) Representative fluorescence images of rhMG53‐647 uptake in WT and Mpeg1‐/‐ iBMDMs at 0 and 10 h. MPEG1 deficiency markedly reduced rhMG53 internalization. (G) Proposed model illustrating that MG53 interacts with membrane protein MPEG1 to regulate MVP–STAT6 signaling, promoting STAT6 phosphorylation, nuclear translocation, and activation of repair‐related M2 macrophage genes.