Cordycepin Ameliorates Renal Interstitial Fibrosis by Inhibiting Drp1-Mediated Mitochondrial Fission.

This study aimed to investigate the mechanisms and specific targets of cordycepin in the treatment of renal fibrosis using a unilateral ischemia-reperfusion (UIR) model. A UIR mouse model was established, followed by intraperitoneal injections of cordycepin and Mdivi-1. Masson's trichrome staining and PAS staining were used to identify renal tubulointerstitial fibrosis and assess the degree of renal injury. Fibrosis markers and mitochondrial dynamics-related proteins were evaluated using Western blotting, while differential gene expression and pathway enrichment were analyzed by RNA-seq. Molecular docking, molecular dynamics simulations and surface plasmon resonance were conducted to validate the specific binding sites of cordycepin on the target protein Drp1. Immunofluorescence and in vitro experiments further elucidated the therapeutic mechanism of cordycepin. In vivo experiments showed that intraperitoneal injection of cordycepin significantly reduced renal inflammation and fibrosis, lowered serum creatinine levels, and decreased collagen deposition. Transcriptome analysis revealed that cordycepin treatment downregulated the mitochondrial fission pathway and upregulated the mitochondrial fusion pathway. Western blotting showed reduced levels of fibrosis markers α-SMA and FN, as well as downregulation of Drp1, MFF, and Fis1, and upregulation of OPA1 and Mfn2. In vitro, cordycepin inhibited TGF-β-induced injury in NRK-52E cells, reducing Drp1 expression and IL-6 secretion. Crosstalk experiments confirmed that decreased IL-6 levels were crucial for cordycepin anti-fibrotic effects by suppressing fibroblast activation. Cordycepin ameliorates renal fibrosis by targeting Drp1 to inhibit mitochondrial fission in injured renal tubular epithelial cells, reducing IL-6 secretion and inhibiting fibroblast activation. © 2025 Sun et al.

Citation

Yingxue Sun, Shi Jin, Jun Chen, Jian Zhang, Yufei Lu, Qiuyu Gu, Zhixin Yan, Weize Chen, Annan Chen, Yi Fang, Wenye Geng, Xialian Xu, Nana Song. Cordycepin Ameliorates Renal Interstitial Fibrosis by Inhibiting Drp1-Mediated Mitochondrial Fission. Drug design, development and therapy. 2025;19:1271-1287

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PMID: 40026334

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