Translational andrology and urology · 2026
Leonurine suppresses renal cell carcinoma progression by targeting the PDK1-mediated Warburg effect.
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Qian Tiaodi, Zhou Xuan, Hu Jiajie
Аннотация
BACKGROUND: Leonurine (Leo), a bioactive alkaloid derived from Leonurus japonicus, has demonstrated anti-tumor potential in various malignancies; however, its specific role and molecular targets in renal cell carcinoma (RCC) remain to be elucidated. In this study, we aim to offer a novel perspective on Leo's role in the treatment of RCC, and to provide guidance for the development of new anti-RCC drugs.
METHODS: The anti-tumor efficacy of Leo was evaluated in RCC cell lines through Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and Transwell assays. In silico prediction via the ChEMBL database was utilized to identify potential molecular targets, which were further validated using microscale thermophoresis (MST), molecular docking, and cell thermal shift assays (CETSA). Glycolytic flux was assessed by measuring the extracellular acidification rate (ECAR), glucose uptake, lactate secretion, and intracellular adenosine triphosphate (ATP) levels. Rescue experiments were employed to confirm the involvement of the pyruvate dehydrogenase kinase 1 (PDK1)-mediated metabolic axis. Subcutaneous xenograft mouse model was used to evaluate the role of Leo in RCC progression.
RESULTS: Leonurine significantly inhibited the proliferation and migration of RCC cells while inducing apoptosis in a dose-dependent manner. Mechanistically, Leo was found to interact directly with PDK1 with high affinity, leading to the downregulation of PDK1 protein levels. Functional studies revealed that Leo effectively suppressed the Warburg effect in RCC cells. Notably, the ectopic overexpression of PDK1 significantly abrogated the inhibitory effects of Leo on cell growth, metastasis, and glycolytic metabolism. Consistently, in vivo experiments demonstrated that Leo administration markedly restricted tumor growth in xenograft mice.
CONCLUSIONS: Leo acts as a novel metabolic inhibitor in RCC by directly targeting the PDK1-mediated glycolytic pathway.
METHODS: The anti-tumor efficacy of Leo was evaluated in RCC cell lines through Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, and Transwell assays. In silico prediction via the ChEMBL database was utilized to identify potential molecular targets, which were further validated using microscale thermophoresis (MST), molecular docking, and cell thermal shift assays (CETSA). Glycolytic flux was assessed by measuring the extracellular acidification rate (ECAR), glucose uptake, lactate secretion, and intracellular adenosine triphosphate (ATP) levels. Rescue experiments were employed to confirm the involvement of the pyruvate dehydrogenase kinase 1 (PDK1)-mediated metabolic axis. Subcutaneous xenograft mouse model was used to evaluate the role of Leo in RCC progression.
RESULTS: Leonurine significantly inhibited the proliferation and migration of RCC cells while inducing apoptosis in a dose-dependent manner. Mechanistically, Leo was found to interact directly with PDK1 with high affinity, leading to the downregulation of PDK1 protein levels. Functional studies revealed that Leo effectively suppressed the Warburg effect in RCC cells. Notably, the ectopic overexpression of PDK1 significantly abrogated the inhibitory effects of Leo on cell growth, metastasis, and glycolytic metabolism. Consistently, in vivo experiments demonstrated that Leo administration markedly restricted tumor growth in xenograft mice.
CONCLUSIONS: Leo acts as a novel metabolic inhibitor in RCC by directly targeting the PDK1-mediated glycolytic pathway.