Effect of isoginkgetin on targeting methylenetetrahydrofolate dehydrogenase 2 to induce ROS-mediated apoptosis in non-small cell lung cancer

  • Phytomedicine. 2026 Jun 16:159:158425. doi: 10.1016/j.phymed.2026.158425.
Chunbo Ma  1 ,  Xing Jin  2 ,  Aofeng Sun  2 ,  Yanmao Wang  3 ,  Xiaofan Hong  2 ,  Yini Xu  2 ,  Yihan Ye  2 ,  Yi Zhou  4 ,  Xiao Zhou  5 ,  Haiyang Zhao  5 ,  Dezhi Cheng  2 ,  Jinfei Chen  6 ,  Chengguang Zhao  7 ,  Lehe Yang  8
Affiliations
  • 1. The 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.
  • 2. The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
  • 3. The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Department of Respiration, Xinfeng county People's Hospital, Ganzhou, Jiangxi 341000, China.
  • 4. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 5. The Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang 325035, China.
  • 6. The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: [email protected].
  • 7. The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: [email protected].
  • 8. The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: [email protected].
PMID: 42361761 DOI: 10.1016/j.phymed.2026.158425
Abstract

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.

Keywords
Apoptosis; Isoginkgetin; MTHFD2; NSCLC; Redox homeostasis.
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