Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal cancers, marked by rapid progression, pronounced chemoresistance, and a complex network of genetic and epigenetic dysregulation. Within this challenging context, sirtuins, NAD+-dependent deacetylases, have emerged as pivotal modulators of key cellular processes that drive pancreatic cancer progression. Each sirtuin contributes uniquely to PDAC pathogenesis. SIRT1 influences apoptosis and chemoresistance through hypoxia, enhancing glycolytic metabolism and HIF-1α signaling, which sustain tumor survival against drugs like gemcitabine. SIRT2, conversely, disrupts cancer cell proliferation by inhibiting eIF5A, while SIRT3 exerts tumor-suppressive effects by regulating mitochondrial ROS and glycolysis. SIRT4 inhibits aerobic glycolysis, and its therapeutic upregulation has shown promise in curbing PDAC progression. Furthermore, SIRT5 modulates glutamine and glutathione metabolism, offering an avenue to disrupt PDAC’s metabolic dependencies. SIRT6 and SIRT7, through their roles in angiogenesis, EMT, and metastasis, represent additional targets, with modulators of SIRT6, such as JYQ-42, showing potential to reduce tumor invasiveness. This review aims to provide a comprehensive exploration of the emerging roles of sirtuins, a family of NAD+-dependent enzymes, as critical regulators within the oncogenic landscape of pancreatic cancer. This review meticulously explores the nuanced involvement of sirtuins in pancreatic cancer, elucidating their contributions to tumorigenesis and suppression through mechanisms such as metabolic reprogramming, the maintenance of genomic integrity and epigenetic modulation. Furthermore, it emphasizes the urgent need for the development of targeted therapeutic interventions aimed at precisely modulating sirtuin activity, thereby enhancing therapeutic efficacy and optimizing patient outcomes in the context of pancreatic malignancies.
胰腺导管腺癌（PDAC）是最致命的癌症之一，其特点是进展迅速、化疗耐药性显著，以及复杂的遗传和表观遗传失调网络。在这一极具挑战性的背景下，sirtuins——一类NAD+依赖的去乙酰化酶——已成为驱动胰腺癌进展的关键细胞过程的核心调节因子。每种sirtuin在PDAC发病机制中均发挥独特作用：SIRT1通过缺氧影响细胞凋亡和化疗耐药，增强糖酵解代谢和HIF-1α信号传导，从而维持肿瘤对吉西他滨等药物的生存抵抗；SIRT2则通过抑制eIF5A破坏癌细胞增殖；SIRT3通过调节线粒体活性氧和糖酵解发挥抑癌作用；SIRT4抑制有氧糖酵解，其治疗性上调已显示出遏制PDAC进展的潜力；SIRT5通过调节谷氨酰胺和谷胱甘肽代谢，为破坏PDAC的代谢依赖性提供了途径；SIRT6和SIRT7则通过其在血管生成、上皮间质转化和转移中的作用成为额外靶点，其中SIRT6调节剂如JYQ-42已显示出降低肿瘤侵袭性的潜力。本综述旨在全面探讨sirtuins（NAD+依赖酶家族）作为胰腺癌致癌环境中的关键调节因子的新兴作用，系统阐述其通过代谢重编程、基因组完整性维持及表观遗传调控等机制在胰腺癌发生与抑制中的精细参与，并强调亟需开发针对sirtuin活性的精准靶向治疗策略，以提升胰腺恶性肿瘤的治疗效果并优化患者预后。
肿瘤(癌症)患者之家