Artesunate Enhances DUSP1‐Dependent Mitochondrial Integrity to Mitigate Renal Fibrosis in Diabetic Kidney Disease

ABSTRACT Renal fibrosis is a hallmark of diabetic kidney disease (DKD), and currently available therapies offer limited efficacy. Artesunate (ART), a repurposed antimalarial agent, has recently demonstrated potential in mitigating renal fibrosis. This study aimed to investigate whether ART protects mitochondrial integrity and attenuates fibrosis in tubular epithelial cells (TECs) via the dual‐specificity phosphatase 1 (DUSP1) pathway. Mitochondrial morphology and DUSP1 expression were examined in kidney tissues from DKD patients and db/db mice. ART (25 mg/kg) was administered to db/db mice to evaluate its in vivo effects on fibrosis, mitochondrial dynamics, and inflammation. In vitro, TECs stimulated with high glucose were used to assess mitochondrial function and fibrotic response after ART treatment. Mechanistic studies included RNA sequencing, molecular docking, and genetic modulation (DUSP1 knockdown and overexpression). Mitochondrial swelling, cristae disruption, and TFAM downregulation were observed in both human DKD samples and db/db mice, correlating with tubulointerstitial fibrosis. ART treatment restored mitochondrial structure, reduced fibrotic markers, and suppressed inflammatory cytokines in vivo. In vitro, ART reversed high‐glucose–induced mitochondrial dysfunction and fibrotic signaling. Mechanistically, ART directly bound to and stabilized DUSP1, thereby inhibiting MAPK signaling. Knockdown of DUSP1 abolished the protective effects of ART, while DUSP1 overexpression mimicked ART's therapeutic actions. Notably, DUSP1 expression was significantly reduced in DKD patients, associated with greater fibrosis and worse renal function. ART attenuates renal fibrosis and restores mitochondrial homeostasis in DKD through DUSP1 stabilization and MAPK pathway inhibition. These findings support ART as a potential therapeutic agent targeting mitochondrial integrity and inflammation in diabetic kidney disease.