Icariin synergistically inhibits glycolysis and mitochondrial energy metabolism in lung cancer in association with the HIF-1α/LONP1 axis.
Abstract
Aim
OF THE STUDY Non-small cell lung cancer (NSCLC) accounts for the vast majority of lung cancer cases and remains a therapeutic challenge due to drug resistance, adverse effects, and metabolic plasticity. Icariin (ICR), a principal bioactive flavonoid from Epimedium, exhibits promising antitumor properties; however, its precise role in modulating cancer energy metabolism remains poorly understood. This study aimed to investigate whether ICR synergistically inhibits glycolysis and mitochondrial metabolism, and whether these effects are associated with the HIF-1α/LONP1 signaling axis in NSCLC.
Materials And Methods
In vitro functional assays were performed to evaluate cell proliferation, migration, invasion, apoptosis, and cell cycle progression in NSCLC cell lines. Integrative proteomics, targeted metabolomics, and Western blotting were employed to assess ICR-associated changes in HIF-1α, glycolytic enzymes (HK2, LDHA), and mitochondrial proteins (LONP1, TFAM, MTCO2). The in vivo antitumor efficacy and underlying metabolic mechanisms were validated using an A549 cell-derived xenograft model in nude mice.
Results
ICR significantly suppressed proliferation, migration, and invasion while promoting apoptosis and G0/G1 cell cycle arrest in NSCLC cells. Multi-omics and biochemical analyses revealed that ICR attenuated both aerobic glycolysis and mitochondrial oxidative phosphorylation, accompanied by downregulation of HIF-1α, HK2, LDHA, LONP1, TFAM, and MTCO2. In vivo xenograft experiments confirmed that ICR treatment markedly inhibited tumor growth and modulated the expression of these key metabolic regulators, with no significant body weight loss observed.
Conclusion
This study demonstrates that ICR simultaneously suppresses glycolysis and mitochondrial energy metabolism, with these effects being associated with downregulation of the HIF-1α/LONP1 axis. These findings provide a novel mechanistic rationale and experimental foundation for metabolism-targeted therapeutic strategies in NSCLC.