Uterine leiomyoma (UL), commonly referred to as benign tumors, is characterized by excessive cell proliferation, extracellular matrix (ECM) accumulation, and the presence of stem cell-like properties. Nicotinamide adenine dinucleotide (NAD+) metabolism, regulated in part by nicotinamide phosphoribosyltransferase (NAMPT), plays a crucial role in these pathological processes and has emerged as a potential therapeutic target. Additionally, redox signaling pathways are integral to the pathogenesis of UL, influencing the dynamics of NAD+ metabolism. This study sought to elucidate the regulatory functions of NAMPT and NAD+ metabolism, in conjunction with redox signaling, in the progression of UL, and to explore potential therapeutic strategies targeting these pathways. Evaluation of NAMPT expression in human UL tissues revealed a positive correlation between elevated NAMPT levels and increased ECM deposition, as well as the expression of stemness markers. The use of FK866 and nicotinamide (NAM), to inhibit NAMPT significantly suppressed UL cell viability and attenuated stem cell-like characteristics. Redox signaling pathways, including those associated with DNA damage, lysosomal function homeostasis, and redox-sensitive phagophore formation, were implicated in the regulation of ECM dynamics, particularly through ECM-targeted inhibition. This study highlights the pivotal roles of NAMPT, NAD+ metabolism, and redox signaling in the pathophysiology of UL. Targeting NAMPT, particularly through the use of inhibitors FK866 and NAM, represents a promising therapeutic approach for mitigating UL progression by modulating redox and ECM dynamics. These findings offer novel insights into UL pathogenesis and establish NAMPT as a compelling target for future clinical investigation.

中文翻译：

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NAMPT 和 NAD + 代谢在子宫平滑肌瘤进展中的调节作用：对 ECM 积累、干性和微环境的影响


子宫肌瘤 （UL），通常称为良性肿瘤，其特征是细胞过度增殖、细胞外基质 （ECM） 积累和干细胞样特性的存在。烟酰胺腺嘌呤二核苷酸 （NAD+） 代谢部分受烟酰胺磷酸核糖转移酶 （NAMPT） 调节，在这些病理过程中起着至关重要的作用，并已成为潜在的治疗靶点。此外，氧化还原信号通路是 UL 发病机制不可或缺的一部分，影响 NAD + 代谢的动力学。本研究旨在阐明 NAMPT 和 NAD+ 代谢与氧化还原信号传导在 UL 进展中的调节功能，并探索针对这些途径的潜在治疗策略。对人 UL 组织中 NAMPT 表达的评估显示，升高的 NAMPT 水平与增加的 ECM 沉积以及干性标志物的表达之间存在正相关。使用 FK866 和烟酰胺 （NAM） 抑制 NAMPT 显着抑制 UL 细胞活力并减弱干细胞样特性。氧化还原信号通路，包括与 DNA 损伤、溶酶体功能稳态和氧化还原敏感吞噬泡形成相关的通路，与 ECM 动力学的调节有关，特别是通过 ECM 靶向抑制。本研究强调了 NAMPT 、 NAD + 代谢和氧化还原信号在 UL 病理生理学中的关键作用。靶向 NAMPT，特别是通过使用抑制剂 FK866 和 NAM，代表了一种很有前途的治疗方法，可通过调节氧化还原和 ECM 动力学来缓解 UL 进展。这些发现为 UL 发病机制提供了新的见解，并将 NAMPT 确立为未来临床研究的令人信服的靶标。