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<p>Diabetic kidney disease (DKD) progression is accelerated by tubulointerstitial inflammation (TI), yet no therapies specifically target this pathogenic process. Xanthotoxol (XT), a natural furanocoumarin with demonstrated anti-inflammatory properties in neuroinflammatory contexts, remains unexplored for its potential in DKD-associated TI. This study explored the pharmacological effects and underlying mechanisms of XT on DKD-associated TI through experiments combined with bioinformatics technology. We found that TI was significantly exacerbated in models of DKD. In vitro experiments showed that XT dose-dependently inhibited the upregulation of inflammatory factors, including Interleukin-6 (IL-6), Interleukin-1-beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) in human renal proximal tubule (HK-2) cells induced by high glucose (HG). Network pharmacology and molecular docking analyses identified heat shock protein 90&#xa0;kDa alpha beta 1 (HSP90αβ1) as a pivotal target of XT in this context. Subsequent mechanistic experiments confirmed the existence of a direct physical interaction between HSP90αβ1 and NOD-like receptor family pyrin domain-containing 3 (NLRP3). A high dose of XT was able to effectively inhibit the upregulation of HSP90αβ1 and NLRP3 expression and their interaction induced by HG. Furthermore, the use of the HSP90αβ1 activator tamoxifen eliminated the inhibitory effect of XT on the production of NLRP3 and downstream pro-inflammatory cytokines. In summary, our study is the first to demonstrate that XT may alleviate the DKD-associated TI by targeting the HSP90αβ1/NLRP3 signaling axis. These results indicate that XT is a promising therapeutic candidate for the treatment of DKD.</p>

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Xanthotoxol alleviates tubulointerstitial inflammation in diabetic kidney disease by targeting the HSP90αβ1/NLRP3 signaling pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月24日

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  • Wenjie Jiang,
  • Hao Yang,
  • Jie Ren,
  • LiDan Tang,
  • Jinhong Gong,
  • Hufeng Fang,
  • Shan Xu,
  • Jiale Pang,
  • Dan Su

摘要

Diabetic kidney disease (DKD) progression is accelerated by tubulointerstitial inflammation (TI), yet no therapies specifically target this pathogenic process. Xanthotoxol (XT), a natural furanocoumarin with demonstrated anti-inflammatory properties in neuroinflammatory contexts, remains unexplored for its potential in DKD-associated TI. This study explored the pharmacological effects and underlying mechanisms of XT on DKD-associated TI through experiments combined with bioinformatics technology. We found that TI was significantly exacerbated in models of DKD. In vitro experiments showed that XT dose-dependently inhibited the upregulation of inflammatory factors, including Interleukin-6 (IL-6), Interleukin-1-beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) in human renal proximal tubule (HK-2) cells induced by high glucose (HG). Network pharmacology and molecular docking analyses identified heat shock protein 90 kDa alpha beta 1 (HSP90αβ1) as a pivotal target of XT in this context. Subsequent mechanistic experiments confirmed the existence of a direct physical interaction between HSP90αβ1 and NOD-like receptor family pyrin domain-containing 3 (NLRP3). A high dose of XT was able to effectively inhibit the upregulation of HSP90αβ1 and NLRP3 expression and their interaction induced by HG. Furthermore, the use of the HSP90αβ1 activator tamoxifen eliminated the inhibitory effect of XT on the production of NLRP3 and downstream pro-inflammatory cytokines. In summary, our study is the first to demonstrate that XT may alleviate the DKD-associated TI by targeting the HSP90αβ1/NLRP3 signaling axis. These results indicate that XT is a promising therapeutic candidate for the treatment of DKD.