The Synthetic Melanocortin Agonist NDP ‐ MSH Ameliorates THSD 7 A ‐Associated Membranous Nephropathy in an Active Immunization Mouse Model

Melanocortin-based therapies have demonstrated protective effects in experimental membranous nephropathy (MN). However, existing evidence is derived exclusively from passive immunization models that lack direct involvement of human MN-associated autoimmunity, limiting translational relevance. A clinically relevant model is essential to more precisely define melanocortin efficacy and mechanisms in MN. To address this gap, we established an active immunization model of THSD7A-associated MN by immunizing mice with recombinant THSD7A antigen. This clinically relevant and accessible model recapitulated cardinal features of human MN, including insidious onset, progressive proteinuria, and characteristic histopathology such as subepithelial immune deposition, complement fixation along glomerular tufts, glomerular basement membrane thickening, and podocyte injury with foot process effacement and loss of homeostatic markers. Rescue treatment with the pan-melanocortin receptor agonist NDP-MSH significantly reduced proteinuria and mitigated glomerular damage and podocyte injury. This was accompanied by a marked reduction in circulating anti-THSD7A autoantibody levels, reduced glomerular immune deposition, and diminished complement activation. Mechanistically, ex vivo treatment of primed B cells isolated from diseased mice demonstrated that NDP-MSH directly inhibited plasma cell differentiation and autoantibody production. This suppression was accompanied by increased expression of microphthalmia-associated transcription factor (MITF) and downregulation of interferon regulatory factor 4 (IRF4), indicating activation of the MITF/IRF4 signaling axis, a pathway implicated in negative regulation of B cell differentiation. Collectively, these findings extend the therapeutic potential of melanocortin signaling to a preclinical model that closely mirrors human MN and provide mechanistic insight into its immunomodulatory actions. These results support further investigation of targeted melanocortin-based therapies for MN.