Disruption of cellular iron homeostasis by SRPX2-IRP1 interaction aggravates renal fibrosis in chronic kidney disease

Disrupted iron homeostasis is a critical pathological feature of chronic kidney disease (CKD) and drives renal fibrosis and disease progression, but the underlying regulatory mechanisms linking iron dysregulation to renal fibrosis remain poorly defined. Here, we identify sushi repeat-containing protein X-linked 2 (SRPX2) as a novel pathogenic regulator of renal fibrosis that dysregulates tubular cellular iron metabolism. Clinical validation revealed that SRPX2 expression was significantly elevated in kidney biopsy tissues and serum samples of CKD patients with various renal pathological types, serving as a potential biomarker for CKD progression. In two classic mouse renal fibrosis models of unilateral ureteral obstruction (UUO) and folic acid (FA)-induced nephropathy, as well as in TGF-β1-stimulated human renal tubular epithelial HK-2 cells, SRPX2 was significantly upregulated in a time- and dose-dependent manner through the TGFβR1/SMAD2/3 signaling pathway. Global and TEC-specific ablation of Srpx2 was sufficient to attenuate kidney injury and fibrosis. Mechanistically, SRPX2 physically interacted with iron regulatory protein 1 (IRP1), a central coordinator of cellular iron homeostasis. This interaction disrupted the IRP1/iron-responsive element regulatory system, leading to decreased expression of iron import protein (TFR1) and increased expression of iron storage (FTH1) and export (FPN) proteins, ultimately triggering intracellular iron dyshomeostasis. Moreover, proteomic and transcriptional profiling of clinical CKD samples and UUO mouse kidneys further confirmed the significant dysregulation of iron ion metabolism during renal fibrosis progression. Notably, therapeutic iron dextran supplementation alleviated UUO-induced renal fibrosis. Collectively, our findings reveal SRPX2 as a key pathogenic factor driving renal fibrosis by disrupting tubular iron homeostasis. Targeting the SRPX2-IRP1 regulatory axis presents a promising therapeutic strategy for slowing CKD progression.