Network Pharmacology, Molecular Docking, Hematological Evaluation, and In Vivo Evidence Support Sakuranetin as a Redox and Inflammation-Modulating Agent Against Skin Tumorigenesis

Introduction: Skin cancer is a growing global health concern, often linked to environmental carcinogens like ultraviolet radiation and chemicals. This study investigated the protective effects of sakuranetin against DMBA-induced skin cancer in mice. Methods: A total of 24 mice were randomly divided into four groups: a control group, a disease control group, and two treatment groups that received sakuranetin orally at 10 mg/kg and 20 mg/kg post-DMBA exposure for eight weeks. Tumorigenesis was evaluated through histopathology, followed by hematological (Hb, RBCs, MCV, WBCs, PCV, and MCH), antioxidant enzyme levels (SOD, CAT, GSH), lipid peroxidation, pro-inflammatory markers (IL-1β, IL-6, TNF-α, COX-2), NF-κB, and caspase-3. Additionally, network pharmacology and molecular docking were performed. Results: Treatment with Sakuranetin restored the abnormal hematological parameters, restored antioxidant enzyme levels (SOD, CAT, GSH), reduced lipid peroxidation, and significantly reduced pro-inflammatory markers, NF-κB, while increased caspase-3. Histological examination confirmed reduced neoplastic changes. Sakuranetin at the dose of 20 mg/kg completely prevents tumor development. Network pharmacology identified 53 potential sakuranetin targets, and molecular docking revealed strong binding affinities with key proteins, including COX-2 (-9.2), TGF-β (-8.5), NF-κB (-8.1), caspase-3 (-6.8), and VEGF (-5.9), which are involved in cancer pathways. Conclusion: Sakuranetin effectively mitigated DMBA-induced skin cancer through antioxidant, anti-inflammatory, and pro-apoptotic mechanisms. These findings suggest its potential as a multi-targeted therapeutic candidate for skin cancer prevention.