Nerolidol-loaded beta-cyclodextrin nanoparticles modulate Nrf-2/Keap1/NF-κB signaling to inhibit DMBA-induced mammary carcinogenesis in Sprague-Dawley rats.

Breast cancer remains a major health concern among women, necessitating innovative therapeutic strategies. This study investigates the effect of nerolidol-loaded β-cyclodextrin nanoparticles (NER-βCD-NPs) on the Nrf-2/Keap1/NF-κB signaling pathway in 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis in Sprague-Dawley rats. Network pharmacology identified 18 key genes linked to nerolidol anticancer action, with pathway enrichment analyses revealing roles in xenobiotic metabolism, antioxidant defense, and inflammatory regulation. Molecular docking demonstrated strong binding affinities of nerolidol with Nrf-2, Keap1, NQO1, HO-1, and NF-κB, supporting its therapeutic relevance. In vivo, DMBA exposure elevated lipid peroxidation and phase I enzyme activity while depleting antioxidants and phase II detoxification enzymes. Oral administration of NER-βCD-NPs (5, 10, and 20 mg/kg b.w.) significantly restored biochemical parameters, reduced tumor burden and incidence, and improved lipid profile and antioxidant enzyme levels. Histopathological observations confirmed the reversal of DMBA-induced mammary tissue damage. Molecular analyses revealed downregulation of NF-κB and Keap1, with concomitant upregulation of Nrf-2, NQO1, and HO-1, indicating effective modulation of oxidative and inflammatory pathways. Western blot and qRT-PCR analyses further validated the molecular impact of NER-βCD-NPs on key signaling molecules. Overall, NER-βCD-NPs exhibit potent chemoprotective effects against DMBA-induced mammary carcinogenesis by targeting the Nrf-2/Keap1/NF-κB, mitigating oxidative stress, and suppressing inflammatory signaling. These results highlight the potential of NER-βCD-NPs as a promising nanotherapeutic approach for breast cancer management.