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<p>Podophyllotoxin (PPT), a potent antitumor natural lignan, is clinically limited by nephrotoxicity, with the microbiome-gut-kidney (MGK) axis’s role unclear. Guided by the Toxicological Evidence Chain (TEC) framework, this study used multi-omics approaches in ICR mice (control, low/high-dose PPT) to explore mechanisms. The physiological indices of mice, health status, renal pathological changes, injury and proinflammatory biomarkers, gut microbiota, metabolism, and transcriptional changes were determined to collect toxicity evidence. Besides, an integrated multi-omics approach, including 16S rRNA gene sequencing, metabolomics coupled with LC–MS/MS, and transcriptomics, was employed to systematically elucidate the potential nephrotoxicity mechanism of PPT. Results showed that PPT significantly induced health deterioration, including reduced activity and body weight, hemorrhage, hunched posture, and severe diarrhea. The dose-dependent nephrotoxicity caused, including decreased kidney organ index, pathological structural changes, and elevated renal injury indices, particularly BUN, Cr, KIM-1, IL-18, and mAlb. Furthermore, gut microbiota dysbiosis (enriched <i>Escherichia-Shigella</i>, depleted <i>Lactobacillus</i>), disrupted tryptophan/ascorbate metabolism, and downregulated key metabolic genes were also observed after PPT intervention. Integrated analysis confirmed gut microbiota dysbiosis mediates PPT-induced nephrotoxicity via the MGK axis. Our research evidence chain implies that PPT promotes intestinal flora dysbiosis, thereby redirecting tryptophan metabolism toward the kynurenine pathway and suppression of the ascorbate and aldarate metabolism pathway abolishes its renoprotective effects simultaneously, triggering amplified inflammatory cascades and ultimately leading to renal dysfunction and nephrotoxicity. This study identifies a novel mechanism, actionable mitigation targets, and supports TEC’s application in toxicological assessment.</p> Graphical abstract <p></p>

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An integrated multi-omics approach for deciphering podophyllotoxin-induced nephrotoxicity via the microbiome-gut-kidney (MGK) axis based on the toxicological evidence (TEC) concept

  • 期刊论文

  • 发表日期：

    2026年5月25日

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  • Xiaole Guo,
  • Yu Wang,
  • Lei Wang,
  • Yan Lei,
  • Ri-na Sa,
  • Lili Li,
  • Shengnan Xia,
  • Xiaoming Lin,
  • Chuanxin Liu,
  • Yuanyang Shao

摘要

Podophyllotoxin (PPT), a potent antitumor natural lignan, is clinically limited by nephrotoxicity, with the microbiome-gut-kidney (MGK) axis’s role unclear. Guided by the Toxicological Evidence Chain (TEC) framework, this study used multi-omics approaches in ICR mice (control, low/high-dose PPT) to explore mechanisms. The physiological indices of mice, health status, renal pathological changes, injury and proinflammatory biomarkers, gut microbiota, metabolism, and transcriptional changes were determined to collect toxicity evidence. Besides, an integrated multi-omics approach, including 16S rRNA gene sequencing, metabolomics coupled with LC–MS/MS, and transcriptomics, was employed to systematically elucidate the potential nephrotoxicity mechanism of PPT. Results showed that PPT significantly induced health deterioration, including reduced activity and body weight, hemorrhage, hunched posture, and severe diarrhea. The dose-dependent nephrotoxicity caused, including decreased kidney organ index, pathological structural changes, and elevated renal injury indices, particularly BUN, Cr, KIM-1, IL-18, and mAlb. Furthermore, gut microbiota dysbiosis (enriched Escherichia-Shigella, depleted Lactobacillus), disrupted tryptophan/ascorbate metabolism, and downregulated key metabolic genes were also observed after PPT intervention. Integrated analysis confirmed gut microbiota dysbiosis mediates PPT-induced nephrotoxicity via the MGK axis. Our research evidence chain implies that PPT promotes intestinal flora dysbiosis, thereby redirecting tryptophan metabolism toward the kynurenine pathway and suppression of the ascorbate and aldarate metabolism pathway abolishes its renoprotective effects simultaneously, triggering amplified inflammatory cascades and ultimately leading to renal dysfunction and nephrotoxicity. This study identifies a novel mechanism, actionable mitigation targets, and supports TEC’s application in toxicological assessment.

Graphical abstract