Over the years, pancreatic cancer has experienced a global surge in incidence and mortality rates, largely attributed to the influence of obesity and diabetes mellitus on disease initiation and progression. In this study, we investigated the pathogenesis of pancreatic cancer in mice subjected to a high-fat diet (HFD) and observed an increase in citric acid expenditure. Notably, citrate treatment demonstrates significant efficacy in promoting tumor cell apoptosis, suppressing cell proliferation, and inhibiting tumor growth in vivo. Our investigations revealed that citrate achieved these effects by releasing secreted protein acidic and rich in cysteine (SPARC) proteins, repolarizing M2 macrophages into M1 macrophages, and facilitating tumor cell apoptosis. Overall, our research highlights the critical role of citric acid as a pivotal metabolite in the intricate relationship between obesity and pancreatic cancer. Furthermore, we uncovered the significant metabolic and immune checkpoint function of SPARC in pancreatic cancer, suggesting its potential as both a biomarker and therapeutic target in treating this patient population.

中文翻译：

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柠檬酸促进胰腺癌细胞中 SPARC 的释放并抑制高脂饮食小鼠胰腺肿瘤的进展

多年来，胰腺癌的全球发病率和死亡率急剧上升，这很大程度上归因于肥胖和糖尿病对疾病发生和进展的影响。在这项研究中，我们研究了高脂饮食（HFD）小鼠胰腺癌的发病机制，并观察到柠檬酸消耗的增加。值得注意的是，柠檬酸盐治疗在促进肿瘤细胞凋亡、抑制细胞增殖和抑制体内肿瘤生长方面表现出显着功效。我们的研究表明，柠檬酸盐通过释放富含半胱氨酸的酸性分泌蛋白 (SPARC)、将 M2 巨噬细胞复极化为 M1 巨噬细胞并促进肿瘤细胞凋亡来实现这些效果。总体而言，我们的研究强调了柠檬酸作为关键代谢物在肥胖与胰腺癌之间复杂关系中的关键作用。此外，我们发现了 SPARC 在胰腺癌中的重要代谢和免疫检查点功能，表明其作为治疗该患者群体的生物标志物和治疗靶点的潜力。