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Peer-reviewedCC BY 4.0Frontiers in Pharmacology

Mechanism-driven nano-therapeutic platform integrating plant-derived compounds and membrane-active peptides reprograms inflammatory, cell cycle arrest, cGAS–STING, and apoptotic gene expression to quench colorectal cancer

  • Doaa Ibrahim1
  • Safaa I. Khater2
  • Ahmed Abdelfattah-Hassan3,4
  • Nouf A. Babteen5
  • Leena S. Alqahtani5
  • Safa H. Qahl5
  • Mahmoud Mostafa6,7
  • Noha Osama El-Shaer8
  • Sherief M. Abdel-Raheem9
  • Norah Alkhayyal5
  • Randah Alghamdi5
  • Nasiruddin Khan10
10 affiliations
  1. 1Department of Nutrition and Clinical Nutrition, Faculty of Veterinary Medicine, Zagazig University
  2. 2Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Zagazig University
  3. 3Department of Veterinary Medicine, College of Applied and Health Sciences, A’Sharqiyah University
  4. 4Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Zagazig University
  5. 5Department of Biological Sciences, College of Science, University of Jeddah
  6. 6Department of Pharmaceutics, Faculty of Pharmacy, Minia University
  7. 7Department of Pharmaceutics, Faculty of Pharmacy, Minia National University
  8. 8Department of Physiology, Faculty of Medicine, Benha University
  9. 9Department of Public Health, College of Veterinary Medicine, King Faisal University
  10. 10Department of Health Sciences, College of Applied and Health Sciences, A’Sharqiyah University
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Abstract

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, and its first-line chemotherapeutic, 5-fluorouracil (5-FU), is constrained by poor tumor selectivity, dose-limiting systemic toxicity, and the frequent emergence of drug resistance. Nanocarrier-based co-delivery of naturally derived, multi-targeted agents offers a promising strategy to enhance efficacy while limiting off-target harm. This study evaluated the antitumor effects of nanoformulated liposomal melittin peptides (LIP-MLT) and niosomal chrysin (NsCR), administered as monotherapy or as combined therapy (LIP-MLT/NsCR), against DMH-induced CRC in a rat model. CRC was induced by subcutaneous injection of DMH (1,2-dimethylhydrazine, 40 mg/kg, twice weekly) for 8 weeks. Sprague-Dawley rats (n = 120) were randomly divided into six groups: healthy control (CON); untreated colorectal tumour (CR-TUM); and DMH-induced rats treated with 5-fluorouracil (CR-TUM + FU5), liposomal melittin (CR-TUM + LIP-MLT), niosomal chrysin (CR-TUM + NsCR), or the combination (CR-TUM + LIP-MLT/NsCR). Oxidant/antioxidant status, inflammatory cytokines, and the transcriptional profiles of inflammatory, cell-cycle-arrest, apoptotic/antiapoptotic, cGAS – STING innate-sensing, mTOR , and angiogenesis/metastasis genes were assessed, together with histopathological and immunohistochemical evaluation. The untreated CR-TUM group showed pronounced tumor-markers elevation, anemia, oxidative damage, and a strong pro-inflammatory, immunosuppressive shift. Relative to CR-TUM, LIP-MLT/NsCR lowered the tumor markers CEA (3.1-fold), CA19-9 (3.5-fold), and CCSA (2.1-fold), and reduced the oxidative markers ROS (2.2-fold), MDA (1.8-fold), and NO (2.2-fold) while raising the antioxidants. It also decreased the pro-inflammatory mediators NF-κB (2.3-fold), IL - 1 β (2.4-fold), and TNF -α (1.7-fold) versus CR-TUM, reversing approximately 71% of the DMH-induced inflammatory signature. At the transcriptional level, the combination produced the strongest upregulation of the pro-apoptotic genes (Caspase-3, Caspase-8, BAX , and p53 ) with concurrent downregulation of the antiapoptotic mediators (Bcl-2, c- FLIP , and Survivin), and marked proliferative and metastatic drivers suppression, including CDK4, CDK6 , cyclin D1, β-catenin, mTOR , MMP -9, and VEGF, alongside restoration of the CDK inhibitors p21 , p27, and KLF4 and normalization of cGAS, STING, and IRF3 mRNA levels. LIP-MLT/NsCR further best-preserved body weight and colon length, lowered diarrhea and rectal-bleeding scores, restored colonic histopathological architecture, and most strongly diminished the immunoexpression of MMP -9 and VEGF relative to untreated cancer tissues. Taken together, the combined LIP-MLT/NsCR nanoformulation attenuated DMH-induced CRC progression to a greater extent than either monotherapy or conventional 5-FU, supporting the combined melittin–chrysin nanoformulation as a promising, multi-targeted strategy against colorectal cancer.

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Cite

BibTeXRIS
BibTeX
@article{ibrahim2026mechanismdriven,
  title = {{Mechanism-driven nano-therapeutic platform integrating plant-derived compounds and membrane-active peptides reprograms inflammatory, cell cycle arrest, cGAS–STING, and apoptotic gene expression to quench colorectal cancer}},
  author = {Doaa Ibrahim and Safaa I. Khater and Ahmed Abdelfattah-Hassan and Nouf A. Babteen and Leena S. Alqahtani and Safa H. Qahl and Mahmoud Mostafa and Noha Osama El-Shaer and Sherief M. Abdel-Raheem and Norah Alkhayyal and Randah Alghamdi and Nasiruddin Khan},
  journal = {Frontiers in Pharmacology},
  year = {2026},
  month = oct,
  doi = {10.3389/fphar.2026.1963760},
  url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1963760/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Mechanism-driven nano-therapeutic platform integrating plant-derived compounds and membrane-active peptides reprograms inflammatory, cell cycle arrest, cGAS–STING, and apoptotic gene expression to quench colorectal cancer
AU  - Doaa Ibrahim
AU  - Safaa I. Khater
AU  - Ahmed Abdelfattah-Hassan
AU  - Nouf A. Babteen
AU  - Leena S. Alqahtani
AU  - Safa H. Qahl
AU  - Mahmoud Mostafa
AU  - Noha Osama El-Shaer
AU  - Sherief M. Abdel-Raheem
AU  - Norah Alkhayyal
AU  - Randah Alghamdi
AU  - Nasiruddin Khan
PY  - 2026
DA  - 2026/10/27
JO  - Frontiers in Pharmacology
DO  - 10.3389/fphar.2026.1963760
UR  - https://www.frontiersin.org/articles/10.3389/fphar.2026.1963760/full
AB  - Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, and its first-line chemotherapeutic, 5-fluorouracil (5-FU), is constrained by poor tumor selectivity, dose-limiting systemic toxicity, and the frequent emergence of drug resistance. Nanocarrier-based co-delivery of naturally derived, multi-targeted agents offers a promising strategy to enhance efficacy while limiting off-target harm. This study evaluated the antitumor effects of nanoformulated liposomal melittin peptides (LIP-MLT) and niosomal chrysin (NsCR), administered as monotherapy or as combined therapy (LIP-MLT/NsCR), against DMH-induced CRC in a rat model. CRC was induced by subcutaneous injection of DMH (1,2-dimethylhydrazine, 40 mg/kg, twice weekly) for 8 weeks. Sprague-Dawley rats (n = 120) were randomly divided into six groups: healthy control (CON); untreated colorectal tumour (CR-TUM); and DMH-induced rats treated with 5-fluorouracil (CR-TUM + FU5), liposomal melittin (CR-TUM + LIP-MLT), niosomal chrysin (CR-TUM + NsCR), or the combination (CR-TUM + LIP-MLT/NsCR). Oxidant/antioxidant status, inflammatory cytokines, and the transcriptional profiles of inflammatory, cell-cycle-arrest, apoptotic/antiapoptotic, cGAS – STING innate-sensing, mTOR , and angiogenesis/metastasis genes were assessed, together with histopathological and immunohistochemical evaluation. The untreated CR-TUM group showed pronounced tumor-markers elevation, anemia, oxidative damage, and a strong pro-inflammatory, immunosuppressive shift. Relative to CR-TUM, LIP-MLT/NsCR lowered the tumor markers CEA (3.1-fold), CA19-9 (3.5-fold), and CCSA (2.1-fold), and reduced the oxidative markers ROS (2.2-fold), MDA (1.8-fold), and NO (2.2-fold) while raising the antioxidants. It also decreased the pro-inflammatory mediators NF-κB (2.3-fold), IL - 1 β (2.4-fold), and TNF -α (1.7-fold) versus CR-TUM, reversing approximately 71% of the DMH-induced inflammatory signature. At the transcriptional level, the combination produced the strongest upregulation of the pro-apoptotic genes (Caspase-3, Caspase-8, BAX , and p53 ) with concurrent downregulation of the antiapoptotic mediators (Bcl-2, c- FLIP , and Survivin), and marked proliferative and metastatic drivers suppression, including CDK4, CDK6 , cyclin D1, β-catenin, mTOR , MMP -9, and VEGF, alongside restoration of the CDK inhibitors p21 , p27, and KLF4 and normalization of cGAS, STING, and IRF3 mRNA levels. LIP-MLT/NsCR further best-preserved body weight and colon length, lowered diarrhea and rectal-bleeding scores, restored colonic histopathological architecture, and most strongly diminished the immunoexpression of MMP -9 and VEGF relative to untreated cancer tissues. Taken together, the combined LIP-MLT/NsCR nanoformulation attenuated DMH-induced CRC progression to a greater extent than either monotherapy or conventional 5-FU, supporting the combined melittin–chrysin nanoformulation as a promising, multi-targeted strategy against colorectal cancer.
SN  - 1663-9812
ER  -