CBL0137 inhibits TFR2-mediated IgA1 deposition in IgA nephropathy.

In IgA nephropathy (IgAN), pathogenic IgA1 deposits in the glomerular mesangium through specific interactions with mesangial cell surface receptors. However, the precise molecular mechanisms underlying this deposition remain incompletely understood. In this study, we observed a significant upregulation of transferrin receptor 2 (TFR2) expression in mesangial cells derived from the kidney tissue of IgAN patients, with TFR2 expression levels positively correlating with disease severity. Mechanistically, TFR2 was found to bind stably to IgA1, as demonstrated by molecular docking, immunofluorescence, and co-immunoprecipitation experiments. Moreover, TFR2 upregulation induced mitochondrial iron overload and promoted mesangial cell proliferation. Through high-throughput drug screening and molecular dynamics simulations, we identified CBL0137 as a small-molecule TFR2 inhibitor, which effectively suppressed TFR2-mediated IgA1 deposition and mesangial cell proliferation in an IgAN mouse model. These findings were further confirmed in human mesangial cells in vitro. Taken together, our results suggest that IgA1 promotes mesangial cell proliferation by upregulating TFR2 expression and inducing mitochondrial iron overload, contributing to IgA1 deposition in IgAN. This study provides novel insights into the molecular mechanisms of IgA1 deposition in mesangial cells and identifies TFR2 as a potential therapeutic target for IgAN.