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Background <p>Cyclophosphamide (Cyclo) is an effective chemotherapeutic agent, but its clinical use is limited by severe cardiotoxicity driven by oxidative stress, inflammation, and apoptosis. Natural antioxidants such as carnosic acid (CA) may offer protection. This study aimed to investigate the protective effects of CA against Cyclo-induced cardiotoxicity in rats and to elucidate the underlying molecular mechanisms.</p> Methods <p>Forty male Wistar rats were divided into four groups: control, CA alone, Cyclo alone, and Cyclo + CA. CA was administered orally at 100&#xa0;mg/kg for 14 days, while Cyclo was injected intraperitoneally at 100&#xa0;mg/kg on day 14. Cardiac injury was assessed using serum biomarkers, histology, immunohistochemistry (NF-κB, TNF-α, IL-1β, caspase-3), RT-PCR (Keap-1, Nrf2, HO-1, Bax, Bcl-2), and oxidative stress markers.</p> Results <p>Cyclo significantly elevated serum cardiac injury markers (CK, troponin, and LDH), as well as hepatic injury markers (ALT and AST), and induced severe histopathological damage, including leukocytic infiltration, congestion, edema, and fibrosis. Mechanistically, Cyclo suppressed the Keap1/Nrf2/HO-1 pathway by downregulating Nrf2 and HO-1 while upregulating Keap-1. Cyclo also depleted antioxidant enzyme activities (SOD, GPx, CAT), increased lipid peroxidation (MDA), activated NF-κB-driven pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and promoted apoptosis via upregulation of Bax and caspase-3 alongside downregulation of Bcl-2. Co-treatment with CA markedly reversed all these pathological changes, restoring antioxidant and Nrf2/HO-1 signaling, reducing inflammatory markers, inhibiting apoptosis, and improving cardiac histology.</p> Conclusion <p>CA effectively attenuates Cyclo-induced cardiotoxicity through its antioxidant, anti-inflammatory, and anti-apoptotic properties. These protective effects are likely associated with modulation of the Keap-1/Nrf2/HO-1 and NF-κB signaling pathways, highlighting CA’s therapeutic potential as a natural cardioprotective agent in chemotherapy-associated cardiac injury.</p> Graphical Abstract <p>Proposed schematic representation of the cardioprotective mechanism of CA against Cyclo-induced cardiotoxicity based on the present findings and previously published literature. Cyclophosphamide exposure leads to cardiac damage through the induction of oxidative stress, inflammation (NF-κB-mediated), and disorganization of cardiac histology, ultimately resulting in cardiotoxicity. Carnosic Acid mitigates this damage by activating the KEAP-1/NRF2/HO-1 pathway. This activation inhibits cytosolic Nrf2 degradation, allowing it to translocate to the nucleus and activate the Antioxidant Response Element (ARE). Concurrently, CA inhibits the NF-κB cascade, reducing the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). The combined effect is a reduction in oxidative stress (↓ROS, ↓MDA), inflammation, and apoptosis (as indicated by modulated Bax, Bcl-2, and Caspase-3), leading to decreased serum injury markers (CK, LDH, Troponin, AST, ALT, MDA), improved cardiac histology, and mitigation of cardiotoxicity.</p>

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Targeting Keap1/Nrf2/Ho-1 Pathway May Explain the Ameliorative Effect of Carnosic Acid against Cyclophosphamide-Induced Cardiotoxicity

  • 期刊论文

  • 发表日期：

    2026年7月20日

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  • Basma Salah,
  • Ahmed shaban Abdelmonsef,
  • Medhat Taha,
  • Emadeldeen Hussin,
  • Eman Mohamad El Nashar,
  • Naira ElAshmouny,
  • Asmaa Mahde Kamel,
  • Mohammed E. Elmitwalli,
  • Ahmed Abdel-monem Elmetwally,
  • Noha M. Halloull,
  • Omnia Hassan Megahed,
  • Rehab Abd El Azeem Esa,
  • Marwa M. Mona,
  • Nehal E. Refaay,
  • Magda E. Ahmed

摘要

Background

Cyclophosphamide (Cyclo) is an effective chemotherapeutic agent, but its clinical use is limited by severe cardiotoxicity driven by oxidative stress, inflammation, and apoptosis. Natural antioxidants such as carnosic acid (CA) may offer protection. This study aimed to investigate the protective effects of CA against Cyclo-induced cardiotoxicity in rats and to elucidate the underlying molecular mechanisms.

Methods

Forty male Wistar rats were divided into four groups: control, CA alone, Cyclo alone, and Cyclo + CA. CA was administered orally at 100 mg/kg for 14 days, while Cyclo was injected intraperitoneally at 100 mg/kg on day 14. Cardiac injury was assessed using serum biomarkers, histology, immunohistochemistry (NF-κB, TNF-α, IL-1β, caspase-3), RT-PCR (Keap-1, Nrf2, HO-1, Bax, Bcl-2), and oxidative stress markers.

Results

Cyclo significantly elevated serum cardiac injury markers (CK, troponin, and LDH), as well as hepatic injury markers (ALT and AST), and induced severe histopathological damage, including leukocytic infiltration, congestion, edema, and fibrosis. Mechanistically, Cyclo suppressed the Keap1/Nrf2/HO-1 pathway by downregulating Nrf2 and HO-1 while upregulating Keap-1. Cyclo also depleted antioxidant enzyme activities (SOD, GPx, CAT), increased lipid peroxidation (MDA), activated NF-κB-driven pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and promoted apoptosis via upregulation of Bax and caspase-3 alongside downregulation of Bcl-2. Co-treatment with CA markedly reversed all these pathological changes, restoring antioxidant and Nrf2/HO-1 signaling, reducing inflammatory markers, inhibiting apoptosis, and improving cardiac histology.

Conclusion

CA effectively attenuates Cyclo-induced cardiotoxicity through its antioxidant, anti-inflammatory, and anti-apoptotic properties. These protective effects are likely associated with modulation of the Keap-1/Nrf2/HO-1 and NF-κB signaling pathways, highlighting CA’s therapeutic potential as a natural cardioprotective agent in chemotherapy-associated cardiac injury.

Graphical Abstract

Proposed schematic representation of the cardioprotective mechanism of CA against Cyclo-induced cardiotoxicity based on the present findings and previously published literature. Cyclophosphamide exposure leads to cardiac damage through the induction of oxidative stress, inflammation (NF-κB-mediated), and disorganization of cardiac histology, ultimately resulting in cardiotoxicity. Carnosic Acid mitigates this damage by activating the KEAP-1/NRF2/HO-1 pathway. This activation inhibits cytosolic Nrf2 degradation, allowing it to translocate to the nucleus and activate the Antioxidant Response Element (ARE). Concurrently, CA inhibits the NF-κB cascade, reducing the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). The combined effect is a reduction in oxidative stress (↓ROS, ↓MDA), inflammation, and apoptosis (as indicated by modulated Bax, Bcl-2, and Caspase-3), leading to decreased serum injury markers (CK, LDH, Troponin, AST, ALT, MDA), improved cardiac histology, and mitigation of cardiotoxicity.