Numerous studies have documented the efficacy of Traditional Chinese Medicine (TCM) as an adjunct therapy in OS treatment, exerting superior anti-tumor effects with fewer side effects. Given this potential, a new study in the Genes & Diseases journal by researchers from The First Affiliated Hospital of Chongqing Medical University, Chongqing University, and Chongqing Hospital of Traditional Chinese Medicine explored the anti-tumor effects of Yanghe Decoction (YHD), a TCM formula with documented but poorly understood clinical potential.

The authors utilized a comprehensive approach—integrating network pharmacology, molecular docking, and extensive in vitro and in vivo experimentation—to elucidate the multi-target mechanisms by which YHD exerts its antitumor effects.
Initial network pharmacology analysis identified 67 active components within YHD, including representative compounds such as (-)-epicatechin and aucubin. These compounds interacted with 101 OS-related targets, with core regulatory nodes including AKT1, TP53, MAPK14, and CASP3 primarily enriched within the PI3K/AKT and MAPK signaling pathways. These pathways regulate reactive oxygen species (ROS), mitochondrial metabolism, and apoptosis, indicating that the modulation of oxidative stress represents a central axis of action. Molecular docking analysis confirmed high binding affinities between these identified targets and the representative chemical constituents of YHD.

Functional assays revealed that YHD selectively inhibits OS cell proliferation, migration, and invasion without inducing cytotoxicity in normal human cell lines, such as liver (LO2) and renal (HK2) cells. The decoction significantly suppressed the expression of the proliferation marker PCNA and induced cell cycle arrest at the G2/M phase by downregulating cyclin B. Furthermore, YHD inhibited the metastatic potential of OS cells by modulating matrix metalloproteinases (MMPs) and suppressing the epithelial-mesenchymal transition (EMT), as evidenced by the downregulation of Snail, Vimentin, and N-cadherin alongside the upregulation of E-cadherin.

A key finding of this study is that YHD orchestrates OS cell death through ROS-induced mitochondrial dysfunction. YHD treatment significantly elevated intracellular ROS levels, resulting in a reduction in mitochondrial DNA abundance, disruption of the mitochondrial membrane potential, and inhibition of ATP production. These mitochondrial perturbations triggered the intrinsic apoptotic pathway, characterized by the release of cytochrome c (Cyt-C) and the subsequent activation of caspase-9, caspase-3, and PARP.

Mechanistically, the study demonstrated that YHD exerts its effects by suppressing the PI3K/AKT pathway while activating p38 MAPK signaling. Western blot analysis confirmed a significant reduction in phosphorylated PI3K and AKT, alongside an increase in phosphorylated p38. The essential roles of these pathways were verified through the use of a PI3K activator and a p38 inhibitor, both of which partially reversed YHD’s inhibitory effects on OS cell viability and migration.

In vivo experiments using orthotopic OS mouse models further corroborated these findings, showing that YHD significantly inhibited primary tumor growth and reduced lung metastasis. YHD also exerted a significant synergistic effect when combined with cisplatin (CDDP), enhancing the sensitivity of OS cells to chemotherapy and further inhibiting tumor progression and metastasis.

In conclusion, YHD inhibits osteosarcoma progression by inducing ROS-mediated mitochondrial dysfunction and modulating the PI3K/AKT and p38 MAPK pathways. These results provide a robust theoretical and experimental basis for YHD as a promising adjuvant therapy to conventional chemotherapy in clinical OS management.

Reference

Title of the original paper: Network pharmacology reveals that Yanghe Decoction inhibits osteosarcoma progression via ROS-induced mitochondrial dysfunction and enhances cisplatin sensitivity
Journal : Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI : https://doi.org/10.1016/j.gendis.2025.101862

Funding Information:

1. First Affiliated Hospital of Chongqing Medical University's "Discipline Summit Plan” (Chongqing, China) (No. cyyy-xkdfjhcgzh-202303)
2. Chongqing Young and Middle-aged Medical High-end Talent Studio (China) (No. cstc2022ycjh-bgzxm0103)
3. Science and Technology Research Program of Chongqing Municipal Education Commission (China) (No. KJZD-M202402802)
4. Horizontal Scientific Research Project of the First Affiliated Hospital of Chongqing Medical and Pharmaceutical College (Chongqing Medical and Pharmaceutical College Of China) (No. 2025YGZKY01)

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