Pancreatic cancer’s substantial impact on cancer-related mortality, responsible for 8% of cancer deaths and ranking fourth in the US, persists despite advancements, with a five-year relative survival rate of only 11%. Forecasts predict a 70% surge in new cases and a 72% increase in global pancreatic cancer-related deaths by 2040. This review explores the intrinsic metabolic reprogramming of pancreatic cancer, focusing on the mevalonate pathway, including cholesterol biosynthesis, transportation, targeting strategies, and clinical studies. The mevalonate pathway, central to cellular metabolism, significantly shapes pancreatic cancer progression. Acetyl coenzyme A (Acetyl-CoA) serves a dual role in fatty acid and cholesterol biosynthesis, fueling acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) development. Enzymes, including acetoacetyl-CoA thiolase, 3-hydroxy-3methylglutaryl-CoA (HMG-CoA) synthase, and HMG-CoA reductase, are key enzymes in pancreatic cancer. Inhibiting HMG-CoA reductase, e.g., by using statins, shows promise in delaying PanIN progression and impeding pancreatic cancer. Dysregulation of cholesterol modification, uptake, and transport significantly impacts tumor progression, with Sterol O-acyltransferase 1 (SOAT1) driving cholesterol ester (CE) accumulation and disrupted low-density lipoprotein receptor (LDLR) expression contributing to cancer recurrence. Apolipoprotein E (ApoE) expression in tumor stroma influences immune suppression. Clinical trials targeting cholesterol metabolism, including statins and SOAT1 inhibitors, exhibit potential anti-tumor effects, and combination therapies enhance efficacy. This review provides insights into cholesterol metabolism’s convergence with pancreatic cancer, shedding light on therapeutic avenues and ongoing clinical investigations.
胰腺癌对癌症相关死亡率具有显著影响，尽管医疗技术不断进步，其仍导致美国8%的癌症死亡病例，在全美癌症死因中位列第四，五年相对生存率仅为11%。预测显示，到2040年全球胰腺癌新发病例将激增70%，相关死亡病例将增加72%。本综述探讨胰腺癌内在代谢重编程机制，重点关注甲羟戊酸通路，包括胆固醇生物合成、转运、靶向策略及临床研究。作为细胞代谢的核心通路，甲羟戊酸通路显著影响胰腺癌进展。乙酰辅酶A在脂肪酸和胆固醇生物合成中发挥双重作用，促进腺泡-导管化生及胰腺上皮内瘤变的发展。乙酰乙酰辅酶A硫解酶、3-羟基-3-甲基戊二酰辅酶A合酶及HMG-CoA还原酶等关键酶在胰腺癌进程中起重要作用。抑制HMG-CoA还原酶（如使用他汀类药物）可延缓胰腺上皮内瘤变进展并抑制胰腺癌发展。胆固醇修饰、摄取和转运的失调显著影响肿瘤进展，其中甾醇O-酰基转移酶1驱动胆固醇酯积累，低密度脂蛋白受体表达紊乱则促进癌症复发。肿瘤基质中载脂蛋白E的表达影响免疫抑制状态。针对胆固醇代谢的临床试验（包括他汀类药物和SOAT1抑制剂）显示出潜在抗肿瘤效应，联合疗法可进一步提升疗效。本综述深入解析胆固醇代谢与胰腺癌的相互作用机制，为治疗路径探索及临床研究提供新的视角。
肿瘤(癌症)患者之家