Liensinine reshapes the immune microenvironment and enhances immunotherapy by reprogramming metabolism through the AMPK-HIF-1α axis in hepatocellular carcinoma

作者：Jiahao Liu, Xuan Zhang, Xiaofei Fan, Peng Liu, Ze Mi, Hongpei Tan, Pengfei Rong · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2025 · DOI：10.1186/s13046-025-03477-6 · 被引用次数：23 · 研究领域：Berberine and alkaloids research、Chromatography in Natural Products、Metabolomics and Mass Spectrometry Studies

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with limited treatment options in advanced stages. Liensinine, a natural alkaloid derived from Nelumbo nucifera, has shown promise as an anticancer agent. However, its underlying mechanisms, particularly in modulating tumor metabolism and immune responses, remain poorly understood. This study aimed to investigate the antitumor effects of Liensinine in HCC, focusing on its ability to modulate metabolic pathways, immune responses, and the tumor microenvironment. METHODS: HCC cell lines (HUH7 and Hep1-6) were treated with Liensinine in vitro to assess cell viability, migration, proliferation, and apoptosis. Metabolic reprogramming was analyzed through RNA sequencing, Seahorse metabolic assays, and glucose/lactate measurements. The effects on immune cells were studied by treating THP-1 macrophages and peripheral blood mononuclear cells (PBMCs) with conditioned media from Liensinine-treated cells. In vivo, subcutaneous xenograft and orthotopic liver cancer models were used to evaluate the therapeutic efficacy of Liensinine combination with radiotherapy and immunotherapy. RESULTS: Liensinine inhibited HCC cell viability, migration, and proliferation, promoting apoptosis and shifting metabolism from glycolysis to oxidative phosphorylation. This metabolic reprogramming was linked to the activation of the AMPK-HIF-1α axis and increased ROS production. Furthermore, Liensinine induced Endoplasmic ...