Mechanism by which CAP regulates the "cold-heat" balance in osteosarcoma model mice: an integrative study of metabolomics, transcriptomics, and network pharmacology.

BACKGROUND: Osteosarcoma (OS) is a prevalent malignant bone cancer in children and adolescents, yet the mechanisms driving its progression and therapeutic resistance remain inadequately understood. Current treatment modalities often overlook the significance of the “cold–heat” imbalance as conceptualized in traditional Chinese medicine (TCM), highlighting a critical gap in integrating TCM principles with modern cancer therapies. OBJECTIVES: We aimed to investigate the therapeutic effects of capsaicin (CAP) on the “cold–heat” imbalance in OS model mice and elucidate the mechanisms involved by utilizing a multiomics approach. METHODS: We employed metabolomics, transcriptomics, and network pharmacology to analyze the impact of CAP on OS progression. Tumor-bearing mice were treated with CAP, and metabolic profiles, tumor volumes, and key molecular targets were assessed. RESULTS: Our findings revealed that CAP significantly shifted the metabolic phenotype of OS model mice from a “cold” state to a “heat” state, resulting in a reduced tumor volume and increased metabolic activity. Notably, CAP was shown to target key pathways involving AKT1, STAT3, NF-κB, EGFR and Caspase 3. CONCLUSION: CAP effectively modulated tumor growth and restored the “cold–heat” balance in OS model mice, providing valuable insights into the potential integration of TCM with conventional oncologic therapies. These findings underscore the importance of multifaceted strategies in developing innovative cancer treatments and contribute to the advancement of translational medicine. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07238-z.