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<p>Bellidifolin (BEL), the primary active compound in <i>Gentianella acuta</i>, demonstrates significant cardioprotective effects. This study aimed to investigate the protective role of BEL against DOX-induced myocardial injury and its mechanisms. Network pharmacology was utilized to identify possible therapeutic targets of BEL for disease treatment. In vivo, 30 C57BL/6 mice were randomly assigned to three experimental groups: Control, DOX, and BEL treatment (DOX + BEL). Mice were orally administered BEL (30&#xa0;mg/kg) for 21 days, with a single intraperitoneal injection of DOX (15&#xa0;mg/kg) on day 14. In vitro, H9c2 cells were used to assess the cardioprotective effects of BEL (50 µM) against DOX-induced toxicity. Cardiac function, myocardial histopathological changes, serum myocardial injury markers, oxidative stress indicators, and apoptosis were evaluated. Western blot analysis was conducted to detect the Nrf2/HO-1 and Galectin-3/NLRP3 pathway proteins. A total of 123 intersection targets were identified between BEL and disease-related proteins, including core targets such as caspase-3, IL-1β, and TNF. GO and KEGG pathway analyses revealed that BEL’s protective effects against DOX-induced myocardial injury were associated with apoptosis, oxidative stress and inflammation. In vivo, BEL treatment improved cardiac function and myocardial histopathological morphology. BEL reduced MDA levels while increasing SOD and GSH-Px activity. Furthermore, BEL alleviated DOX-induced mitochondrial damage. BEL also decreased the apoptosis rate and modulated the expression of Caspase-3, Bax, and Bcl-2. Additionally, BEL activated the Nrf2/HO-1 pathway, as evidenced by increased nuclear translocation of Nrf2, upregulation of Nrf2, HO-1, GCLM, and NQO1 proteins, and a simultaneous decrease in Keap1 levels. BEL also suppressed the Galectin-3/NLRP3 inflammatory pathway, reducing the expression of Galectin-3, NLRP3, ASC, Caspase-1, IL-18, and IL-1β. In vitro, BEL treatment significantly decreased ROS levels induced by DOX. Overall, BEL mitigated DOX-induced cardiotoxicity by inhibiting oxidative stress, inflammation, and apoptosis via the Nrf2/HO-1 and Galectin-3/NLRP3 pathways.</p> Graphical abstract <p></p>

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Bellidifolin mitigates doxorubicin-induced myocardial injury via regulating oxidative stress, inflammation, and apoptosis: a combination of network pharmacology and experiments

  • 期刊论文

  • 发表日期：

    2026年3月10日

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  • Ying Cao,
  • Yutao Jia,
  • Rongrong Chen,
  • Cheng Dai,
  • Hongyao Ge,
  • Shenhan Duan,
  • Aiying Li,
  • Jiangli Wu

摘要

Bellidifolin (BEL), the primary active compound in Gentianella acuta, demonstrates significant cardioprotective effects. This study aimed to investigate the protective role of BEL against DOX-induced myocardial injury and its mechanisms. Network pharmacology was utilized to identify possible therapeutic targets of BEL for disease treatment. In vivo, 30 C57BL/6 mice were randomly assigned to three experimental groups: Control, DOX, and BEL treatment (DOX + BEL). Mice were orally administered BEL (30 mg/kg) for 21 days, with a single intraperitoneal injection of DOX (15 mg/kg) on day 14. In vitro, H9c2 cells were used to assess the cardioprotective effects of BEL (50 µM) against DOX-induced toxicity. Cardiac function, myocardial histopathological changes, serum myocardial injury markers, oxidative stress indicators, and apoptosis were evaluated. Western blot analysis was conducted to detect the Nrf2/HO-1 and Galectin-3/NLRP3 pathway proteins. A total of 123 intersection targets were identified between BEL and disease-related proteins, including core targets such as caspase-3, IL-1β, and TNF. GO and KEGG pathway analyses revealed that BEL’s protective effects against DOX-induced myocardial injury were associated with apoptosis, oxidative stress and inflammation. In vivo, BEL treatment improved cardiac function and myocardial histopathological morphology. BEL reduced MDA levels while increasing SOD and GSH-Px activity. Furthermore, BEL alleviated DOX-induced mitochondrial damage. BEL also decreased the apoptosis rate and modulated the expression of Caspase-3, Bax, and Bcl-2. Additionally, BEL activated the Nrf2/HO-1 pathway, as evidenced by increased nuclear translocation of Nrf2, upregulation of Nrf2, HO-1, GCLM, and NQO1 proteins, and a simultaneous decrease in Keap1 levels. BEL also suppressed the Galectin-3/NLRP3 inflammatory pathway, reducing the expression of Galectin-3, NLRP3, ASC, Caspase-1, IL-18, and IL-1β. In vitro, BEL treatment significantly decreased ROS levels induced by DOX. Overall, BEL mitigated DOX-induced cardiotoxicity by inhibiting oxidative stress, inflammation, and apoptosis via the Nrf2/HO-1 and Galectin-3/NLRP3 pathways.

Graphical abstract