Nicotinamide adenine dinucleotide (NAD+) is an important cofactor for both metabolic and signaling pathways, with the dysregulation of NAD+levels acting as a driver for diseases such as neurodegeneration, cancers, and metabolic diseases. NAD+plays an essential role in regulating the growth and progression of cancers by controlling important cellular processes including metabolism, transcription, and translation. NAD+regulates several metabolic pathways such as glycolysis, the citric acid (TCA) cycle, oxidative phosphorylation, and fatty acid oxidation by acting as a cofactor for redox reactions. Additionally, NAD+acts as a cofactor for ADP-ribosyl transferases and sirtuins, as well as regulating cellular ADP-ribosylation and deacetylation levels, respectively. The cleavage of NAD+by CD38—an NAD+hydrolase expressed on immune cells—produces the immunosuppressive metabolite adenosine. As a result, metabolizing and maintaining NAD+levels remain crucial for the function of various cells found in the tumor microenvironment, hence its critical role in tissue homeostasis. The NAD+levels in cells are maintained by a balance between NAD+biosynthesis and consumption, with synthesis being controlled by the Preiss–Handler, de novo, and NAD+salvage pathways. The primary source of NAD+synthesis in a variety of cell types is directed by the expression of the enzymes central to the three biosynthesis pathways. In this review, we describe the role of NAD+metabolism and its synthesizing and consuming enzymes’ control of cancer cell growth and immune responses in gynecologic cancers. Additionally, we review the ongoing efforts to therapeutically target the enzymes critical for NAD+homeostasis in gynecologic cancers.
烟酰胺腺嘌呤二核苷酸（NAD+）是代谢与信号通路中的重要辅因子，其水平失调是神经退行性疾病、癌症及代谢性疾病等疾病的重要驱动因素。NAD+通过调控代谢、转录和翻译等关键细胞过程，在癌症的生长与进展中发挥核心作用。作为氧化还原反应的辅因子，NAD+参与调节糖酵解、三羧酸循环、氧化磷酸化及脂肪酸氧化等多种代谢途径。此外，NAD+还作为ADP-核糖基转移酶和去乙酰化酶的辅因子，分别调控细胞ADP-核糖基化与去乙酰化水平。免疫细胞表面表达的NAD+水解酶CD38通过裂解NAD+产生免疫抑制代谢物腺苷。因此，代谢调控与维持NAD+水平对于肿瘤微环境中各类细胞的功能至关重要，这也决定了其在组织稳态中的关键作用。细胞内NAD+水平通过生物合成与消耗的动态平衡维持，其合成受Preiss-Handler通路、从头合成通路及补救合成通路调控。不同细胞类型中NAD+合成的主要来源取决于这三条生物合成通路核心酶的表达差异。本综述系统阐述了NAD+代谢及其合成与消耗相关酶在妇科癌症中对癌细胞生长和免疫应答的调控作用，并总结了目前针对妇科癌症中NAD+稳态关键酶的治疗策略研究进展。
Biological Functions and Therapeutic Potential of NAD+Metabolism in Gynecological Cancers
肿瘤(癌症)患者之家