State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Signal Transduct Target Ther. 2022 Sep 1;7(1):303. doi: 10.1038/s41392-022-01097-6.
Endothelial-to-mesenchymal transition (EndoMT), the process wherein endothelial cells lose endothelial identity and adopt mesenchymal-like phenotypes, constitutes a critical contributor to cardiac fibrosis. The phenotypic plasticity of endothelial cells can be intricately shaped by alteration of metabolic pathways, but how endothelial cells adjust cellular metabolism to drive EndoMT is incompletely understood. Here, we identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) as a critical driver of EndoMT via triggering abnormal glycolysis and compromising mitochondrial respiration. Pharmacological suppression of PFKFB3 with salvianolic acid C (SAC), a phenolic compound derived from Salvia miltiorrhiza, attenuates EndoMT and fibrotic response. PFKFB3-haplodeficiency recapitulates the anti-EndoMT effect of SAC while PFKFB3-overexpression augments the magnitude of EndoMT and exacerbates cardiac fibrosis. Mechanistically, PFKFB3-driven glycolysis compromises cytoplasmic nicotinamide adenine dinucleotide phosphate (reduced form, NADPH) production via hijacking glucose flux from pentose phosphate pathway. Efflux of mitochondrial NADPH through isocitrate/α-ketoglutarate shuttle replenishes cytoplasmic NADPH pool but meanwhile impairs mitochondrial respiration by hampering mitochondrial iron-sulfur cluster biosynthesis. SAC disrupts PFKFB3 stability by accelerating its degradation and thus maintains metabolic homeostasis in endothelial cells, underlying its anti-EndoMT effects. These findings for the first time identify the critical role of PFKFB3 in triggering EndoMT by driving abnormal glycolysis in endothelial cells, and also highlight the therapeutic potential for pharmacological intervention of PFKFB3 (with SAC or other PFKFB3 inhibitors) to combat EndoMT-associated fibrotic responses via metabolic regulation.
内皮细胞向间充质转化（EndoMT），即内皮细胞丧失内皮特征并获得间充质样表型的过程，是心脏纤维化的关键贡献者。内皮细胞的表型可塑性可以通过代谢途径的改变而复杂地塑造，但是内皮细胞如何调整细胞代谢来驱动 EndoMT 尚不完全清楚。在这里，我们发现 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶 3（PFKFB3）通过触发异常糖酵解和损害线粒体呼吸来作为 EndoMT 的关键驱动因素。用来源于丹参的酚类化合物丹酚酸 C（SAC）抑制 PFKFB3 的药理学作用可以减弱 EndoMT 和纤维化反应。PFKFB3 单倍体缺陷可再现 SAC 的抗 EndoMT 作用，而 PFKFB3 过表达则增强 EndoMT 的幅度并加剧心脏纤维化。从机制上讲，PFKFB3 驱动的糖酵解通过从戊糖磷酸途径劫持葡萄糖通量来损害细胞质烟酰胺腺嘌呤二核苷酸磷酸（还原形式，NADPH）的产生。通过异柠檬酸/α-酮戊二酸穿梭将线粒体 NADPH 流出以补充细胞质 NADPH 池，但同时通过阻碍线粒体铁硫簇生物合成来损害线粒体呼吸。SAC 通过加速其降解来破坏 PFKFB3 的稳定性，从而维持内皮细胞的代谢平衡，这是其抗 EndoMT 作用的基础。这些发现首次确定了 PFKFB3 通过驱动内皮细胞异常糖酵解在触发 EndoMT 中的关键作用，并强调了通过代谢调节来进行药理学干预 PFKFB3（用 SAC 或其他 PFKFB3 抑制剂）以对抗 EndoMT 相关纤维化反应的治疗潜力。
