Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Nepetin suppresses HBV-associated hepatocellular carcinoma metastasis by regulating the HBx/HIF-1α-mediated autophagy axis.
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Liao Mianmian, Du Haiyan, Zhong Qiusheng, Zhang Yu, Zhang Yi, Wang Zhijuan, Qin Yiheng, Chen Bo, Chen Tuantuan, Zhang Huanhuan, Yuan Weiqu, Huang Danping, Zhou Hua, Tong Guangdong
Аннотация
BACKGROUND: Hepatocellular carcinoma (HCC) arising from chronic Hepatitis B virus (HBV) infection has a high metastatic potential, driven largely by the viral oncoprotein Hepatitis B Virus X Protein (HBx) and a hypoxic tumor microenvironment. Therapeutic strategies targeting these underlying oncogenic mechanisms remain an unmet clinical need.
PURPOSE: Nepetin, a naturally occurring flavonoid with known anti-inflammatory and antitumor activities, has not been evaluated for efficacy against HBV-associated HCC metastasis. Therefore, this study aimed to investigate its antimetastatic potential and underlying molecular mechanisms.
STUDY DESIGN: The antimetastatic effects and molecular targets of Nepetin were evaluated using complementary in vitro and in vivo models of HBV-associated HCC.
METHODS: The antimetastatic effects of Nepetin were assessed in vitro using HBV-positive HCC cell lines and in vivo using an orthotopic liver xenograft model and a tail vein injection metastasis model. Mechanistic studies were conducted using western blotting, molecular docking, cellular thermal shift assay and surface plasmon resonance assays.
RESULTS: Nepetin treatment significantly reduced migration and invasion of HBV-HCC cells in vitro by approximately 45% and 50%, respectively, at 10 µM, and suppressed intrahepatic and pulmonary metastasis in vivo, without apparent toxicity. Mechanistically, Nepetin disrupted the interaction between HBx and HIF-1α, leading to reduced hypoxia-inducible factor-1α (HIF-1α), thereby reducing HIF-1α protein stability and transcriptional activity and subsequently suppressed the downstream prometastatic autophagic flux.
CONCLUSION: The findings identify Nepetin as a candidate compound that inhibits HBV-HCC metastasis by targeting the HBx/HIF-1α/autophagy signaling cascade. These findings provide a mechanistic rationale for targeting this pathway and support further evaluation of the translational potential of Nepetin in metastatic HBV-HCC.
PURPOSE: Nepetin, a naturally occurring flavonoid with known anti-inflammatory and antitumor activities, has not been evaluated for efficacy against HBV-associated HCC metastasis. Therefore, this study aimed to investigate its antimetastatic potential and underlying molecular mechanisms.
STUDY DESIGN: The antimetastatic effects and molecular targets of Nepetin were evaluated using complementary in vitro and in vivo models of HBV-associated HCC.
METHODS: The antimetastatic effects of Nepetin were assessed in vitro using HBV-positive HCC cell lines and in vivo using an orthotopic liver xenograft model and a tail vein injection metastasis model. Mechanistic studies were conducted using western blotting, molecular docking, cellular thermal shift assay and surface plasmon resonance assays.
RESULTS: Nepetin treatment significantly reduced migration and invasion of HBV-HCC cells in vitro by approximately 45% and 50%, respectively, at 10 µM, and suppressed intrahepatic and pulmonary metastasis in vivo, without apparent toxicity. Mechanistically, Nepetin disrupted the interaction between HBx and HIF-1α, leading to reduced hypoxia-inducible factor-1α (HIF-1α), thereby reducing HIF-1α protein stability and transcriptional activity and subsequently suppressed the downstream prometastatic autophagic flux.
CONCLUSION: The findings identify Nepetin as a candidate compound that inhibits HBV-HCC metastasis by targeting the HBx/HIF-1α/autophagy signaling cascade. These findings provide a mechanistic rationale for targeting this pathway and support further evaluation of the translational potential of Nepetin in metastatic HBV-HCC.