吉西他滨是胰腺癌（PC）的一线化疗药物，但它容易产生快速耐药性。提高PC对吉西他滨的敏感性长期以来一直是研究的焦点。禁食干预可能会增强化疗的效果并提供新的选择。已知 SIRT7 通过翻译后修饰将新陈代谢与各种细胞过程联系起来。我们发现 PC 细胞中 SIRT7 的上调与不良预后和吉西他滨耐药相关。 RNA-seq 和 ATAC-seq 数据的交叉分析表明 GLUT3 可能是 SIRT7 的下游靶基因。随后的研究表明，SIRT7 直接与 GLUT3 的增强子区域相互作用，使 H3K122 去琥珀酰化。我们小组的另一项研究表明，GLUT3可以在乳腺癌细胞中转运吉西他滨。在这里，我们发现 GLUT3 KD 降低了 PC 细胞对吉西他滨的敏感性，并且 SIRT7 KD 相关的吉西他滨敏化可以通过 GLUT3 KD 逆转。虽然模仿禁食会导致 PC 细胞中 SIRT7 表达上调，但敲低 SIRT7 可通过上调 GLUT3 表达来增强对吉西他滨的敏感性。我们使用小鼠异种移植模型进一步证实了 SIRT7 缺陷在禁食条件下对吉西他滨敏感性的影响。总之，我们的研究表明，SIRT7 可以通过与其增强子结合并改变 H3K122 琥珀酰化水平来调节 GLUT3 表达，从而影响 PC 细胞中的吉西他滨敏感性。此外，将 SIRT7 敲低与禁食相结合可能会提高吉西他滨的疗效。这揭示了 SIRT7 影响 PC 中吉西他滨敏感性的新机制，并为吉西他滨的临床联合治疗提供创新策略。版权所有 © 2024。由 Elsevier B.V. 出版。

Gemcitabine serves as a first-line chemotherapeutic treatment for pancreatic cancer (PC), but it is prone to rapid drug resistance. Increasing the sensitivity of PC to gemcitabine has long been a focus of research. Fasting interventions may augment the effects of chemotherapy and present new options. SIRT7 is known to link metabolism with various cellular processes through post-translational modifications. We found upregulation of SIRT7 in PC cells is associated with poor prognosis and gemcitabine resistance. Cross-analysis of RNA-seq and ATAC-seq data suggested that GLUT3 might be a downstream target gene of SIRT7. Subsequent investigations demonstrated that SIRT7 directly interacts with the enhancer region of GLUT3 to desuccinylate H3K122. Our group's another study revealed that GLUT3 can transport gemcitabine in breast cancer cells. Here, we found GLUT3 KD reduces the sensitivity of PC cells to gemcitabine, and SIRT7 KD-associated gemcitabine-sensitizing could be reversed by GLUT3 KD. While fasting mimicking induced upregulation of SIRT7 expression in PC cells, knocking down SIRT7 enhanced sensitivity to gemcitabine through upregulating GLUT3 expression. We further confirmed the effect of SIRT7 deficiency on the sensitivity of gemcitabine under fasting conditions using a mouse xenograft model. In summary, our study demonstrates that SIRT7 can regulate GLUT3 expression by binding to its enhancer and altering H3K122 succinylation levels, thus affecting gemcitabine sensitivity in PC cells. Additionally, combining SIRT7 knockdown with fasting may improve the efficacy of gemcitabine. This unveils a novel mechanism by which SIRT7 influences gemcitabine sensitivity in PC and offer innovative strategies for clinical combination therapy with gemcitabine.Copyright © 2024. Published by Elsevier B.V.