The Regulatory Targets and Mechanisms of Ginsenoside Rh2 for NSCLC

The Regulatory Targets and Mechanisms of Ginsenoside Rh2 for NSCLC


In the presence of oxygen, tumors produce adenosine triphosphate (ATP) through glycolysis instead of mitochondrial oxidative phosphorylation, a phenomenon known as the “Warburg effect”. Aerobic glycolysis caused by an altered tumor microenvironment is an important factor contributing to malignant tumor progression. Ginsenoside Rh2 (Rh2) can specifically reverse the shift from tumor aerobic glycolysis to oxidative phosphorylation to modulate the metabolic behavior of non-small cell lung cancer (NSCLC), ultimately promoting the “benignization” of NSCLC.

The suppressive impacts of Rh2 on the malignant progression of NSCLC

Rh2 inhibits the proliferation, invasion and migration, while promoting the apoptosis of NSCLC cells. Meanwhile, Rh2 treatment represses tumor lymph angiogenesis, as manifested by the obviously reduced expression of CD31. Moreover, Rh2 hinders the metastasis of NSCLC by inhibiting the epithelial mesenchymal transition (EMT), as evidenced by the upregulation of E-cadherin and downregulation of N-cadherin in lung tissues post Rh2 treatment.


Underlying targets and mechanisms of Rh2 against NSCLC

Rh2 hampers NSCLC aerobic glycolytic capacity, including glucose uptake and lactate production, through the HIF1-α/PDK4 pathway. Specifically, Rh2 targets hypoxia-inducible factor HIF-1α to downregulate its expression, subsequently reducing the expression of PDK4, a pivotal enzyme during the glucose oxidation process. By this way, Rh2 further suppresses aerobic glycolysis, promotes mitochondrial aerobic oxidative process, and stimulates the production of reactive oxygen species (ROS), thereby promoting tumor cells to enter the normal apoptotic program.


The efficacy of Rh2 combined with DCA in NSCLC

Sodium dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDKs), has been commonly used in clinical practice as an anticancer drug targeting glycolysis, yet it has hepatotoxicity and neurotoxicity at high doses. Notably, the combination of Rh2 with DCA dramatically reverses the biometabolic behaviors of tumors, and further reduces the dosage of DCA, which decreases the toxicity of DCA, greatly increasing the drug efficacy.



Rh2 shifts tumor metabolism from aerobic glycolysis to oxidative phosphorylation through regulating the HIF1-α/PDK4 axis in NSCLCs. It activates the apoptotic program of NSCLCs and exerts a potentiating and toxicity-reducing effect when used in combination with chemotherapeutic agents DCA, hinting its potential as an adjuvant against tumors.


Liu X, Li J, Huang Q, et al. Ginsenoside Rh2 shifts tumor metabolism from aerobic glycolysis to oxidative phosphorylation through regulating the HIF1-α/PDK4 axis in non-small cell lung cancer. Mol Med. 2024;30(1):56. Published 2024 Apr 26. doi:10.1186/s10020-024-00813-y

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