In a groundbreaking exploration into the realm of osteosarcoma (OS) therapy, researchers from The First Affiliated Hospital of Chongqing Medical University, alongside collaborators from Chongqing University and the Chongqing Hospital of Traditional Chinese Medicine, have unveiled the profound antitumor mechanisms of Yanghe Decoction (YHD), a traditional Chinese medicine formula. Published in the high-impact journal Genes & Diseases, this study integrates state-of-the-art network pharmacology, molecular docking, and meticulous in vitro and in vivo experimentation to dissect how YHD orchestrates a multifaceted assault on osteosarcoma progression.
Osteosarcoma, a malignant bone tumor predominately affecting adolescents, remains a therapeutic challenge due to its aggressive nature and propensity for metastasis. Conventional chemotherapeutic regimens such as cisplatin (CDDP) provide some clinical benefit but are often culpable for severe side effects and eventual drug resistance. This urgent clinical impasse has propelled investigations into adjunct therapies with enhanced efficacy and tolerability. YHD has been clinically recognized for decades for its therapeutic potential, but its molecular underpinnings in OS treatment remained obscure until now.
The researchers employed a comprehensive network pharmacology approach that identified 67 bioactive constituents within YHD. Among these, (-)-epicatechin and aucubin emerged as principal compounds with high target engagement. The integrated target prediction delineated 101 overlapping OS-associated molecular targets, largely involving pivotal oncogenic regulators such as AKT1, TP53, MAPK14, and CASP3. Enrichment analyses spotlighted the PI3K/AKT and MAPK signaling pathways as the principal conduits mediating YHD’s therapeutic action.
Molecular docking simulations underscored the robust binding affinities between YHD’s active ingredients and key OS protein targets, confirming the compound-target interactions postulated by the network pharmacology framework. Notably, the docking heatmap revealed darker blue shading correlating with more stable binding free energies, highlighting the structural compatibility and potential inhibitory potency of these phytochemicals on oncogenic targets.
Cellular functional assays further elucidated YHD’s selective cytotoxic profile. Remarkably, YHD inhibited proliferation, migration, and invasion of osteosarcoma cells without compromising viability in normal human liver (LO2) and kidney (HK2) cell lines. The reduction of the proliferation marker PCNA and the induction of G2/M cell cycle arrest, mediated by downregulated cyclin B expression, pinpoint mechanistic checkpoints through which YHD impedes tumor growth.
Exploring the metastatic cascade, YHD modulated the epithelial-mesenchymal transition (EMT) by downregulating transcription factors and proteins such as Snail, Vimentin, and N-cadherin, while restoring E-cadherin expression. This molecular switch impairs OS cells’ invasive capabilities and disrupts matrix remodeling through attenuation of matrix metalloproteinases (MMPs), fundamentally curtailing metastatic potential.
Central to YHD’s antitumor efficacy is its induction of reactive oxygen species (ROS)-mediated mitochondrial dysfunction. YHD treatment precipitated a significant increase in intracellular ROS, catalyzing a decline in mitochondrial DNA copy number, destabilization of mitochondrial membrane potential, and consequential inhibition of ATP synthesis. This mitochondrial distress activated intrinsic apoptotic pathways as evidenced by the release of cytochrome c, followed by sequential activation of caspase-9, caspase-3, and PARP cleavage, culminating in programmed cancer cell death.
Mechanistic interrogation revealed that YHD concurrently suppresses the oncogenic PI3K/AKT signaling cascade while activating the stress-responsive p38 MAPK pathway. Western blot analyses highlighted decreased phosphorylation of PI3K and AKT alongside an upregulation of phosphorylated p38 MAPK in OS cells treated with YHD. The roles of these pathways were further substantiated by pharmacological manipulation: a PI3K activator and a p38 inhibitor partially rescued cell viability and migration impeded by YHD, verifying their critical regulatory functions.
Translating these in vitro findings, orthotopic osteosarcoma mouse models treated with YHD demonstrated markedly reduced primary tumor volume and diminished lung metastatic foci, affirming YHD’s potent antineoplastic capacity in vivo. Strikingly, combining YHD with cisplatin resulted in a synergistic inhibition of tumor progression and metastasis, underscoring YHD’s utility in sensitizing OS cells to chemotherapy and mitigating chemoresistance.
This comprehensive study not only unveils the molecular intricacies of YHD’s anti-osteosarcoma activity but also positions YHD as a promising adjuvant therapeutic candidate that could revolutionize OS clinical management. By harnessing the power of traditional medicinal compounds and integrating modern molecular insights, the therapeutic landscape for osteosarcoma could be significantly augmented.
Future clinical trials and translational studies are warranted to validate these preclinical observations and optimize YHD formulations for human application. The potential of YHD to reduce chemotherapy-associated toxicity while enhancing antitumor efficacy represents a pivotal advancement in holistic cancer treatment paradigms.
In summary, Yanghe Decoction exerts its therapeutic effects against osteosarcoma through a multifaceted mechanism involving ROS-induced mitochondrial dysfunction, strategic suppression of the PI3K/AKT pathway, and activation of p38 MAPK signaling. This integrative molecular modulation culminates in decreased tumor proliferation, invasion, and metastasis, alongside enhanced chemotherapy response, heralding a novel era for TCM-derived therapeutics in oncological precision medicine.
Subject of Research: Osteosarcoma treatment via traditional Chinese medicine (Yanghe Decoction) elucidating molecular mechanisms.
Article Title: Network pharmacology reveals that Yanghe Decoction inhibits osteosarcoma progression via ROS-induced mitochondrial dysfunction and enhances cisplatin sensitivity.
Web References: Available through ScienceDirect: https://www.sciencedirect.com/journal/genes-and-diseases
References:
Huang Y, Tang D, Zhao R, Zhang J, Qu X, Li N, Ren Y, Luo X. Network pharmacology reveals that Yanghe Decoction inhibits osteosarcoma progression via ROS-induced mitochondrial dysfunction and enhances cisplatin sensitivity. Genes & Diseases. DOI: 10.1016/j.gendis.2025.101862.
Image Credits: Yanran Huang, Dagang Tang, Runhan Zhao, Jun Zhang, Xiao Qu, Ningdao Li, Yi Ren, Xiaoji Luo
Keywords: Osteosarcoma, Yanghe Decoction, Traditional Chinese Medicine, ROS, Mitochondrial Dysfunction, PI3K/AKT Pathway, p38 MAPK, Molecular Docking, Chemotherapy Sensitization, Apoptosis, Cell Cycle Arrest, Metastasis Inhibition
