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Effect of isoginkgetin on targeting methylenetetrahydrofolate dehydrogenase 2 to induce ROS-mediated apoptosis in
Chunbo Ma1, Xing Jin2, Aofeng Sun2
1The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; The Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang 325035, China.
Background:
Non-small cell lung cancer (NSCLC) remains a major cause of cancer mortality. Isoginkgetin, a natural biflavonoid, has shown pharmacological potential, yet its antitumor mechanisms in NSCLC are not well defined.
Purpose:
This study investigated the antitumor activity of isoginkgetin in NSCLC and explored its molecular targets and underlying mechanisms.
Study Design:
Cell-based assays and in vivo xenograft models combined with transcriptomic profiling, redox analyses, and in silico target identification/validation.
Methods:
Cell-based assays were performed to evaluate the effects of isoginkgetin on NSCLC cell growth, migration, apoptosis, and epithelial-mesenchymal transition (EMT). Transcriptome profiling and redox analyses were conducted to assess mechanistic pathways. Target identification was conducted through in silico screening, followed by drug-target binding validation and functional characterization, including further validation through Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) overexpression and silencing. The antitumor efficacy of isoginkgetin was further examined in NSCLC xenograft models, and the safety was assessed through acute toxicity experiments.
Results:
Isoginkgetin suppressed proliferation and migration, induced apoptosis, and blocked EMT in NSCLC cells. It disrupted redox homeostasis by enhancing oxidative stress, mediated by elevated reactive oxygen species (ROS) accumulation and activating endoplasmic reticulum (ER) stress and mitochondrial apoptosis. MTHFD2 was identified as a direct target of isoginkgetin, which binds to MTHFD2 and suppresses its functional role, ultimately leading to NADPH depletion and oxidative stress. Silencing MTHFD2 reproduced the effects of isoginkgetin, while overexpression of MTHFD2 partly attenuated these effects. In vivo, isoginkgetin markedly reduced tumor growth without systemic toxicity.
Conclusion:
Isoginkgetin exerts potent antitumor effects in NSCLC by targeting MTHFD2 and inducing redox imbalance, supporting its promise as a novel therapeutic candidate.
Insights
Isoginkgetin, a natural compound, effectively combats non-small cell lung cancer (NSCLC) by targeting MTHFD2. This action disrupts cellular redox balance and induces cancer cell death, showing promise for new NSCLC therapies.
Area of Science:
- Natural product chemistry
- Oncology
- Molecular biology
Background:
- Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality.
- Isoginkgetin, a natural biflavonoid, exhibits potential pharmacological activity, but its antitumor mechanisms in NSCLC require elucidation.
Purpose of the Study:
- To investigate the antitumor effects of isoginkgetin in NSCLC.
- To identify the molecular targets and mechanisms underlying isoginkgetin's activity in NSCLC.
Main Methods:
- Utilized cell-based assays and in vivo xenograft models.
- Employed transcriptomic profiling, redox analyses, and in silico target identification.
- Validated MTHFD2 as a direct target through overexpression and silencing studies.
Main Results:
- Isoginkgetin inhibited NSCLC cell proliferation, migration, and epithelial-mesenchymal transition (EMT), while inducing apoptosis.
- The compound disrupted redox homeostasis, increased reactive oxygen species (ROS), and triggered endoplasmic reticulum (ER) and mitochondrial stress.
- Isoginkgetin directly targeted and inhibited MTHFD2, leading to NADPH depletion and oxidative stress, with significant tumor growth reduction in vivo without systemic toxicity.
Conclusions:
- Isoginkgetin demonstrates potent antitumor activity against NSCLC.
- The mechanism involves targeting MTHFD2 and inducing redox imbalance.
- Isoginkgetin shows promise as a novel therapeutic candidate for NSCLC.
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