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<p>Gambogic acid (GA), a natural xanthonoid compound, has attracted attention for its potential anticancer activity. This study investigated the molecular targets and anticancer effects of GA against lung cancer through computational and experimental approaches. Physicochemical and ADME analysis showed that gambogic acid is highly lipophilic (consensus LogP = 6.13) with poor aqueous solubility (ESOL LogS − 7.92) and predicted low gastrointestinal absorption, while acting as a P-glycoprotein substrate and potential inhibitor of CYP2C9 and CYP3A4. Drug-likeness analysis indicated one Lipinski violation and a bioavailability score of 0.56. Bioinformatics analysis using GeneCards, GSE, and CTD databases identified six key targets involved in lung cancer progression: AKT, RPS6KB1, BCL2, BAX, CASPASE-3, and CASPASE-9. Molecular docking demonstrated strong interactions between GA and these targets, with the highest binding affinity observed for RPS6KB1 (− 8.7&#xa0;kcal/mol), by hydrogen bonds with HIS1032 and ASN1098. In vitro experiments in A549 lung cancer cells revealed that GA exhibited significant cytotoxicity with an IC<sub>50</sub> value of 90 µM. AO/EtBr staining showed increased apoptotic cells, while DAPI staining confirmed nuclear condensation and chromatin fragmentation following GA treatment. GA also significantly inhibited cell migration, reducing migration from 71% in control cells to 32.5% in treated cells. Furthermore, oxidative stress analysis showed decreased antioxidant enzyme levels (SOD and catalase) and increased lipid peroxidation (LPO) in treated cells. Our findings indicate that GA suppresses lung cancer cell proliferation and migration by inducing oxidative stress and apoptosis through modulation of the AKT–RPS6KB1 signalling pathway, highlighting its potential as a therapeutic candidate for lung cancer.</p>

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Molecular and metabolic dysregulation of lung cancer in developing anti-tumor activity by gambogic acid mediated mTOR signaling: in vitro and computational study

  • 期刊论文

  • 发表日期：

    2026年7月15日

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  • Su Bo,
  • Yongsheng Liao,
  • Xiaofen Chen,
  • Li Liu,
  • Feng Pang,
  • Lei Zhou

摘要

Gambogic acid (GA), a natural xanthonoid compound, has attracted attention for its potential anticancer activity. This study investigated the molecular targets and anticancer effects of GA against lung cancer through computational and experimental approaches. Physicochemical and ADME analysis showed that gambogic acid is highly lipophilic (consensus LogP = 6.13) with poor aqueous solubility (ESOL LogS − 7.92) and predicted low gastrointestinal absorption, while acting as a P-glycoprotein substrate and potential inhibitor of CYP2C9 and CYP3A4. Drug-likeness analysis indicated one Lipinski violation and a bioavailability score of 0.56. Bioinformatics analysis using GeneCards, GSE, and CTD databases identified six key targets involved in lung cancer progression: AKT, RPS6KB1, BCL2, BAX, CASPASE-3, and CASPASE-9. Molecular docking demonstrated strong interactions between GA and these targets, with the highest binding affinity observed for RPS6KB1 (− 8.7 kcal/mol), by hydrogen bonds with HIS1032 and ASN1098. In vitro experiments in A549 lung cancer cells revealed that GA exhibited significant cytotoxicity with an IC50 value of 90 µM. AO/EtBr staining showed increased apoptotic cells, while DAPI staining confirmed nuclear condensation and chromatin fragmentation following GA treatment. GA also significantly inhibited cell migration, reducing migration from 71% in control cells to 32.5% in treated cells. Furthermore, oxidative stress analysis showed decreased antioxidant enzyme levels (SOD and catalase) and increased lipid peroxidation (LPO) in treated cells. Our findings indicate that GA suppresses lung cancer cell proliferation and migration by inducing oxidative stress and apoptosis through modulation of the AKT–RPS6KB1 signalling pathway, highlighting its potential as a therapeutic candidate for lung cancer.