Yin Dongge, Chen Hongyue, Jing Xiaohong, Lin Shuting, Sun Yufei, Chang Rongrong, Feng Yang, Dong Xiaoxv, Qu Changhai, Ni Jian, Yin Xingbin
School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China.
Nutrients. 2025 Aug 29;17(17):2809. doi: 10.3390/nu17172809.
Cucurbitacin B (CuB) is a relatively unique and valuable component in plants of the Cucurbitaceae family due to its diverse and remarkable physiological activities, but its specific mechanisms in regulating tumor metabolism and immune response remain unclear. The hypoxic tumor microenvironment (TME) of pancreatic cancer induces metabolic reprogramming in cancer cells, causing them to rely on glycolysis for energy. LDHA, a key enzyme in glycolysis, can suppress glycolysis and tumor growth when inhibited.
The objective of this study was to investigate the mechanism of CuB against pancreatic cancer and its effect on the immune system.
In this study, cell migration/invasion assays, immunofluorescence, ELISA, Western blot, CETSA, flow cytometry, mouse models, and metabolomic and transcriptomic analyses were utilized to systematically elucidate the mechanism by which CuB inhibits pancreatic cancer and activates the immune system.
This study confirms that CuB inhibits pancreatic cancer by suppressing the PI3K/Akt/mTOR pathway and activating PINK1/Parkin to induce mitophagy, thereby inhibiting cell migration, invasion, and proliferation. It downregulates the expression of LDHA to block glycolysis, reduce lactate production and efflux, and improve the acidic TME. CuB also induces ICD to activate dendritic cells, promote CD8+ T-cell and M1 macrophage infiltration, and reduce the levels of regulatory T cells. Metabolomic and transcriptomic analyses validate CuB's dual effects on metabolic reprogramming and immune activation.
This study, for the first time, reveals that CuB induces mitophagy via the PI3K/Akt/mTOR and PINK1/Parkin pathways to selectively eliminate damaged mitochondria and suppress tumor energy metabolism. CuB inhibits pancreatic cancer through a triple mechanism-inducing mitophagy, inhibiting glycolysis, and activating immunity-which provides innovative insights for pancreatic cancer therapy.
葫芦素B（CuB）是葫芦科植物中一种相对独特且有价值的成分，因其具有多样且显著的生理活性，但其在调节肿瘤代谢和免疫反应中的具体机制仍不清楚。胰腺癌的缺氧肿瘤微环境（TME）诱导癌细胞发生代谢重编程，使其依赖糖酵解获取能量。乳酸脱氢酶A（LDHA）是糖酵解中的关键酶，受到抑制时可抑制糖酵解和肿瘤生长。
本研究旨在探讨CuB抗胰腺癌的机制及其对免疫系统的影响。
在本研究中，利用细胞迁移/侵袭试验、免疫荧光、酶联免疫吸附测定（ELISA）、蛋白质印迹法、热蛋白质组分析（CETSA）、流式细胞术、小鼠模型以及代谢组学和转录组学分析，系统地阐明CuB抑制胰腺癌并激活免疫系统的机制。
本研究证实，CuB通过抑制PI3K/Akt/mTOR通路并激活PINK1/Parkin诱导线粒体自噬，从而抑制胰腺癌，进而抑制细胞迁移、侵袭和增殖。它下调LDHA的表达以阻断糖酵解，减少乳酸生成和外排，并改善酸性TME。CuB还诱导免疫原性细胞死亡（ICD）以激活树突状细胞，促进CD8 + T细胞和M1巨噬细胞浸润，并降低调节性T细胞水平。代谢组学和转录组学分析验证了CuB对代谢重编程和免疫激活的双重作用。
本研究首次揭示，CuB通过PI3K/Akt/mTOR和PINK1/Parkin通路诱导线粒体自噬，以选择性清除受损线粒体并抑制肿瘤能量代谢。CuB通过诱导线粒体自噬、抑制糖酵解和激活免疫的三重机制抑制胰腺癌，为胰腺癌治疗提供了创新性见解。
