Integrated strategies of network pharmacology, transcriptomics, and computational and experimental validation reveal
Haichuan Miao1, Baolong Liu2, Xinfang Pan3
1Dalian Medical University, Dalian, 116044, China.
Objective:
Osteosarcoma (OS), the most common primary malignant bone tumor, exhibits poor prognosis, underscoring the need for new therapies. Juglone, a natural naphthoquinone, shows therapeutic promise; however, the effects of juglone on OS and underlying mechanisms remain to be elucidated.
Materials And Methods:
In vitro experiments were validated using U2OS and HOS cell lines. Network pharmacology predicted juglone-OS targets, followed by protein-protein interaction (PPI) network construction and GO/KEGG enrichment analysis. Transcriptomics analysis was further confirmed. Molecular docking was performed using AutoDock Tools and Discovery Studio. Molecular dynamics simulations (MD) using GROMACS confirmed the stability of the juglone-target complex. In vivo experiments clarified the effect of juglone in vivo. ADME/T was profiled using Swiss and Protox.
Results:
Juglone inhibited OS cell viability, promoted apoptosis, suppressed proliferation and migration, and induced G2/M arrest. A total of 234 targets were identified; PPI highlighted key interactors (TP53, AKT1, BCL2, CTNNB1, STAT3). Enrichment analyses revealed associations with oxidative stress and PI3K/AKT pathways. Molecular docking showed high-affinity binding to PI3K and AKT1, confirmed stable by molecular dynamics. Mechanistically, juglone inhibits OS via the ROS/PI3K/AKT pathway. In vivo, it potently inhibited tumor growth in xenograft models with short-term biosafety. ADME/T profiling indicated favorable pharmacokinetics but potential toxicity risks.
Conclusion:
This study first demonstrates juglone's anti-OS efficacy via the ROS/PI3K/AKT pathway. In vivo studies confirm potent tumor suppression with short-term safety, supporting its clinical promise for OS treatment.
Insights
Juglone, a natural compound, effectively inhibits osteosarcoma (OS) growth by targeting the ROS/PI3K/AKT pathway. This study shows promising anti-OS efficacy and tumor suppression with short-term safety in vivo.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Osteosarcoma (OS) is a primary bone cancer with a poor prognosis, necessitating novel therapeutic strategies.
- Juglone, a natural naphthoquinone, presents potential therapeutic value, but its effects and mechanisms in OS require detailed investigation.
Purpose of the Study:
- To elucidate the anti-osteosarcoma effects of juglone.
- To investigate the underlying molecular mechanisms of juglone's action in OS.
- To evaluate the in vivo efficacy and safety of juglone for OS treatment.
Main Methods:
- In vitro studies utilized OS cell lines (U2OS, HOS).
- Network pharmacology, PPI analysis, and transcriptomics identified juglone-OS targets and pathways.
- Molecular docking and dynamics simulations assessed juglone-target interactions.
- In vivo xenograft models evaluated juglone's anti-tumor effect and biosafety.
- ADME/T profiling predicted pharmacokinetic and toxicity profiles.
Main Results:
- Juglone suppressed OS cell viability, proliferation, and migration while inducing apoptosis and G2/M arrest.
- Network analysis identified 234 targets, highlighting TP53, AKT1, and BCL2.
- Juglone demonstrated high-affinity binding to PI3K and AKT1, inhibiting the ROS/PI3K/AKT pathway.
- In vivo studies showed potent tumor growth inhibition with short-term safety.
- Pharmacokinetic profiling indicated favorable ADME properties with potential toxicity concerns.
Conclusions:
- Juglone exhibits significant anti-osteosarcoma efficacy through the ROS/PI3K/AKT signaling pathway.
- In vivo studies confirm juglone's potent tumor suppression capabilities and short-term safety.
- Juglone demonstrates clinical promise as a therapeutic agent for osteosarcoma.
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