The control of the intracellular pH is vital for the survival of all organisms. Membrane transporters, both at the plasma and intracellular membranes, are key players in maintaining a finely tuned pH balance between intra- and extracellular spaces, and therefore in cellular homeostasis. V-ATPase is a housekeeping ATP-driven proton pump highly conserved among prokaryotes and eukaryotes. This proton pump, which exhibits a complex multisubunit structure based on cell type-specific isoforms, is essential for pH regulation and for a multitude of ubiquitous and specialized functions. Thus, it is not surprising that V-ATPase aberrant overexpression, mislocalization, and mutations in V-ATPase subunit-encoding genes have been associated with several human diseases. However, the ubiquitous expression of this transporter and the high toxicity driven by its off-target inhibition, renders V-ATPase-directed therapies very challenging and increases the need for selective strategies. Here we review emerging evidence linking V-ATPase and both inherited and acquired human diseases, explore the therapeutic challenges and opportunities envisaged from recent data, and advance future research avenues. We highlight the importance of V-ATPases with unique subunit isoform molecular signatures and disease-associated isoforms to design selective V-ATPase-directed therapies. We also discuss the rational design of drug development pipelines and cutting-edge methodological approaches toward V-ATPase-centered drug discovery. Diseases like cancer, osteoporosis, and even fungal infections can benefit from V-ATPase-directed therapies.

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关于 V-ATPase 在人类疾病中的作用的新见解：治疗挑战和机遇

细胞内 pH 值的控制对于所有生物的生存至关重要。质膜和细胞内膜上的膜转运蛋白是维持细胞内和细胞外空间之间微调 pH 平衡的关键参与者，因此也是细胞稳态的关键。V-ATPase 是一种管家 ATP 驱动的质子泵，在原核生物和真核生物中高度保守。这种质子泵表现出基于细胞类型特异性亚型的复杂多亚基结构，对于 pH 调节和多种普遍存在的特殊功能至关重要。因此，V-ATPase 异常过度表达、错误定位和 V-ATPase 亚基编码基因突变与多种人类疾病有关也就不足为奇了。然而，这种转运蛋白的普遍表达及其脱靶抑制导致的高毒性使 V-ATPase 导向的治疗变得非常具有挑战性，并增加了对选择性策略的需求。在这里，我们回顾了将 V-ATPase 与遗传性和获得性人类疾病联系起来的新证据，探索从最近的数据中设想的治疗挑战和机遇，并推进未来的研究途径。我们强调了具有独特亚基异构体分子特征和疾病相关异构体的 V-ATPase 对设计选择性 V-ATPase 导向疗法的重要性。我们还讨论了药物开发管道的合理设计和以 V-ATPase 为中心的药物发现的尖端方法论方法。癌症、骨质疏松症甚至真菌感染等疾病都可以从 V-ATPase 导向的疗法中受益。