胰腺癌是一种恶性程度极高的消化道肿瘤，然而，由于胰腺癌的高耐药性，迫切需要寻找更有效的抗胰腺癌药物。石蒜碱是一种天然植物生物碱，对多种肿瘤具有抗肿瘤作用。本研究旨在探讨石蒜碱对胰腺癌的治疗作用并阐明其潜在的分子机制。两种胰腺癌细胞系PANC-1和BxPC- 3、使用CCK8测定、集落形成测定、5-乙炔基-2'-脱氧尿苷（EdU）掺入测定、流式细胞术和蛋白质印迹法研究石蒜碱对胰腺癌的体外治疗效果。采用转录组测序和基因集富集分析（GSEA）分析石蒜碱处理后差异表达的基因和通路。通过分子对接、实时定量PCR（qRT-PCR）、油红O染色、小干扰RNA（siRNA）转染等实验进一步验证差异表达基因和通路。利用荷瘤小鼠模型进行体内实验，研究石蒜碱对胰腺癌的抑制作用和毒性。石蒜碱抑制胰腺癌细胞的增殖，引起G2/M期周期阻滞并诱导细胞凋亡。转录组测序和GSEA表明，石蒜碱对胰腺癌的抑制作用与脂肪酸代谢有关，而乙醛脱氢酶3A1（ALDH3A1）是脂肪酸代谢过程中显着富集的靶标。 ALDH3A1在胰腺癌中表达显着上调，且与预后密切相关。分子对接表明石蒜碱与 ALDH3A1 强烈结合。进一步的研究表明，石蒜碱抑制胰腺癌细胞的脂肪酸氧化（FAO）过程，并通过 ALDH3A1 诱导细胞生长抑制和凋亡。石蒜碱对荷瘤小鼠也显示出显着的抑制作用。重要的是，它不会对小鼠的肝脏和肾脏产生明显的毒性，证明了其作为安全抗肿瘤药物的治疗潜力。 Lycorine 通过靶向 ALDH3A1 抑制胰腺癌细胞增殖，阻断细胞周期并诱导细胞凋亡。首次将FAO抑制作用确定为石蒜碱抗癌作用的可能机制。这些发现丰富了胰腺癌靶向治疗理论，拓展了我们对石蒜碱药理靶点的认识，并为探索其天然成分提供了参考。版权所有 © 2023 Elsevier GmbH。版权所有。

Pancreatic cancer is an extremely malignant digestive tumor, however, owing to its high drug resistance of pancreatic cancer, the search for more effective anti-pancreatic cancer drugs is urgently needed. Lycorine, an alkaloid of natural plant origin, exerts antitumor effects on a variety of tumors.This study aimed to investigate the therapeutic effect of lycorine on pancreatic cancer and elucidate its potential molecular mechanism.Two pancreatic cancer cell lines, PANC-1 and BxPC-3, were used to investigate the therapeutic effects of lycorine on pancreatic cancer in vitro using the CCK8 assay, colony formation assay, 5-Ethynyl-2'- deoxyuridine (EdU) incorporation assay, flow cytometry, and western blotting. Transcriptome sequencing and gene set enrichment analysis (GSEA) were used to analyze the differentially expressed genes and pathways after lycorine treatment. Molecular docking, quantitative real-time PCR (qRT-PCR), oil red O staining, small interfering RNA (siRNA) transfection, and other experiments were performed to further validate the differentially expressed genes and pathways. In vivo experiments were conducted to investigate lycorine's inhibitory effects and toxicity on pancreatic cancer using a tumor-bearing mouse model.Lycorine inhibited the proliferation of pancreatic cancer cells, caused G2/M phase cycle arrest and induced apoptosis. Transcriptome sequencing and GSEA showed that lycorine inhibition of pancreatic cancer was associated with fatty acid metabolism, and aldehyde dehydrogenase 3A1 (ALDH3A1) was a significantly enriched target in the fatty acid metabolism process. ALDH3A1 expression was significantly upregulated in pancreatic cancer and was closely associated with prognosis. Molecular docking showed that lycorine binds strongly to ALDH3A1. Further studies revealed that lycorine inhibited the fatty acid oxidation (FAO) process in pancreatic cancer cells and induced cell growth inhibition and apoptosis through ALDH3A1. Lycorine also showed significant suppressive effects in tumor-bearing mice. Importantly, it did not result in significant toxicity to liver and kidney of mice, demonstrating its therapeutic potential as a safe antitumor agent.Lycorine inhibited pancreatic cancer cell proliferation, blocked the cell cycle, and induced apoptosis by targeting ALDH3A1. FAO inhibition was identified for the first time as a possible mechanism for the anticancer effects of lycorine. These findings enrich the theory of targeted therapy for pancreatic cancer, expand our understanding of the pharmacological targets of lycorine, and provide a reference for exploring its natural components.Copyright © 2023 Elsevier GmbH. All rights reserved.