POSTN promotes ferroptosis and contributes to the pathogenesis of IgA nephropathy via GPX4 downregulation

IgA nephropathy (IgAN) is a prevalent glomerular disease characterized by mesangial deposition of IgA1-containing immune complexes, yet its underlying molecular mechanisms remain incompletely understood. In this study, we integrated bioinformatics analyses of two public datasets (GSE104948 and GSE93798) to identify key differentially expressed genes (DEGs) associated with IgAN. Periostin (POSTN) emerged as a hub gene, exhibiting significant upregulation in IgAN samples and correlating with histopathological severity. Functional enrichment revealed that overlapping DEGs are involved in extracellular matrix organization, immune response, and signaling pathways relevant to renal pathology. Immunohistochemical and immunofluorescence analyses confirmed increased POSTN and decreased GPX4 expression in renal biopsies from IgAN patients, indicating enhanced Ferroptosis. In vitro, IgA1 stimulation of human mesangial cells (HMCs) elevated POSTN expression and induced Ferroptosis, evidenced by increased oxidative stress, mitochondrial damage, and reduced cell viability. Knockdown of POSTN ameliorated these effects by restoring glutathione levels and reducing lipid peroxidation, while POSTN overexpression exacerbated Ferroptosis. Notably, treatment with the Ferroptosis inhibitor ferrostatin-1 reversed POSTN-induced cellular damage. Our findings suggest that POSTN promotes IgAN progression by facilitating Ferroptosis through GPX4 downregulation, highlighting a novel pathogenic mechanism. Targeting POSTN-mediated Ferroptosis may provide promising therapeutic strategies for IgAN. This study advances our understanding of IgAN molecular pathology and offers potential biomarkers and intervention targets to improve patient outcomes.

Ferroptosis; Glutathione peroxidase 4 (GPX4); IgA nephropathy (IgAN); Oxidative stress; Periostin (POSTN).