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Background <p>Cyclophosphamide (CPM) is a chemotherapy agent extensively utilized in clinical settings; however, its therapeutic efficacy is frequently compromised by pronounced adverse effects, particularly nephrotoxicity and cardiotoxicity. Esculetin (ESC), a naturally occurring coumarin derivative endowed with antioxidant and anti-inflammatory characteristics, has demonstrated potential as a protective agent across various pathological models.</p> Objectives <p>The primary objective of this study was to explore the nephroprotective and cardioprotective properties of ESC within a rat model exhibiting CPM-induced toxicity, while concurrently elucidating the molecular mechanisms involved, with a particular emphasis on the modulation of antioxidant responses and inflammatory pathways.</p> Methods <p>The cytotoxicity and antioxidant efficacy of ESC were evaluated in vitro. In the in vivo component of the study, rats were stratified into distinct groups and subjected to treatment with CPM either solely or in conjunction with ESC. Assessments of renal and cardiac functionality were conducted via biochemical assays, analyses of antioxidant enzyme activities, histopathological examinations, immunohistochemical evaluations, and quantitative polymerase chain reaction.</p> Results <p>Administration of CPM led to considerable renal and cardiac impairment, as evidenced by heightened markers indicative of oxidative stress and inflammation. The pretreatment with ESC significantly ameliorated these detrimental effects, as illustrated by improved biochemical parameters, preservation of tissue architecture, increased antioxidant enzyme activity, diminished inflammatory markers, and modulation of NRF2, NLRP3, IL-18, and IL-1β gene expression.</p> Conclusion <p>ESC demonstrates substantial nephroprotective and cardioprotective effects against CPM-induced toxicity, likely attributable to the enhancement of antioxidant defenses and the inhibition of inflammatory signaling pathways. These findings underscore the therapeutic promise of ESC in alleviating organ damage associated with CPM exposure.</p> Graphical Abstract <p></p>

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Therapeutic potential of esculetin in attenuating kidney and heart damage caused by cyclophosphamide: insights into NRF2 activation and NLRP3 inhibition

  • 期刊论文

  • 发表日期：

    2025年9月28日

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  • Prathap Srirangan,
  • Mukul Shyam,
  • Vidya Radhakrishnan,
  • Shankha Shubhra Ghosh,
  • Sabina Evan Prince

摘要

Background

Cyclophosphamide (CPM) is a chemotherapy agent extensively utilized in clinical settings; however, its therapeutic efficacy is frequently compromised by pronounced adverse effects, particularly nephrotoxicity and cardiotoxicity. Esculetin (ESC), a naturally occurring coumarin derivative endowed with antioxidant and anti-inflammatory characteristics, has demonstrated potential as a protective agent across various pathological models.

Objectives

The primary objective of this study was to explore the nephroprotective and cardioprotective properties of ESC within a rat model exhibiting CPM-induced toxicity, while concurrently elucidating the molecular mechanisms involved, with a particular emphasis on the modulation of antioxidant responses and inflammatory pathways.

Methods

The cytotoxicity and antioxidant efficacy of ESC were evaluated in vitro. In the in vivo component of the study, rats were stratified into distinct groups and subjected to treatment with CPM either solely or in conjunction with ESC. Assessments of renal and cardiac functionality were conducted via biochemical assays, analyses of antioxidant enzyme activities, histopathological examinations, immunohistochemical evaluations, and quantitative polymerase chain reaction.

Results

Administration of CPM led to considerable renal and cardiac impairment, as evidenced by heightened markers indicative of oxidative stress and inflammation. The pretreatment with ESC significantly ameliorated these detrimental effects, as illustrated by improved biochemical parameters, preservation of tissue architecture, increased antioxidant enzyme activity, diminished inflammatory markers, and modulation of NRF2, NLRP3, IL-18, and IL-1β gene expression.

Conclusion

ESC demonstrates substantial nephroprotective and cardioprotective effects against CPM-induced toxicity, likely attributable to the enhancement of antioxidant defenses and the inhibition of inflammatory signaling pathways. These findings underscore the therapeutic promise of ESC in alleviating organ damage associated with CPM exposure.

Graphical Abstract