胰腺癌（PC）是一种高度致命的恶性肿瘤，常表现为代谢重编程，导致治疗易感性。然而，异常胆固醇代谢对PC发展和进展的影响机制仍然不清楚。在本研究中，我们发现鱼藤萜环氧化酶（SQLE）是PC生长中胆固醇代谢的关键介质。我们观察到PC组织中SQLE的显著上调，其高表达与患者不良结局相关。我们的功能实验表明，SQLE能够促进细胞增殖，在体外诱导细胞周期进程，抑制凋亡，同时在体内促进肿瘤生长。机制上，我们发现SQLE具有双重作用。首先，其抑制导致鱼藤萜积累引起的内质网（ER）应激和随后的凋亡。其次，其增强了新的胆固醇合成并维持脂 rafts的稳定性，进而激活Src/PI3K/Akt信号通路。值得注意的是，使用SQLE抑制剂有效抑制了PC细胞增殖和异种移植瘤生长。总结起来，本研究揭示了SQLE作为一种促进PC生长的新型癌基因，通过减轻ER应激和激活脂 rafts调节的Src/PI3K/Akt信号通路来发挥作用，突显了SQLE作为PC治疗靶点的潜力。© 2023年。作者（们）。

Pancreatic cancer (PC), a highly lethal malignancy, commonly exhibits metabolic reprogramming that results in therapeutic vulnerabilities. Nevertheless, the mechanisms underlying the impacts of aberrant cholesterol metabolism on PC development and progression remain elusive. In this study, we found that squalene epoxidase (SQLE) is a crucial mediator of cholesterol metabolism in PC growth. We observed a profound upregulation of SQLE in PC tissues, and its high expression was correlated with poor patient outcomes. Our functional experiments demonstrated that SQLE facilitated cell proliferation, induced cell cycle progression, and inhibited apoptosis in vitro, while promoting tumor growth in vivo. Mechanistically, SQLE was found to have a dual role. First, its inhibition led to squalene accumulation-induced endoplasmic reticulum (ER) stress and subsequent apoptosis. Second, it enhanced de novo cholesterol biosynthesis and maintained lipid raft stability, thereby activating the Src/PI3K/Akt signaling pathway. Significantly, employing SQLE inhibitors effectively suppressed PC cell proliferation and xenograft tumor growth. In summary, this study reveals SQLE as a novel oncogene that promotes PC growth by mitigating ER stress and activating lipid raft-regulated Src/PI3K/Akt signaling pathway, highlighting the potential of SQLE as a therapeutic target for PC.© 2023. The Author(s).