Zhang Xuexi, Liu Xue, Qiao Yujie, Rabata Anas, Liu Ningshan, Yao Changfu, Parimon Tanyalak, Chen Danica, Chen Peter, Stripp Barry, Gardell Stephen J, Jiang Dianhua, Noble Paul W, Liang Jiurong
bioRxiv. 2025 Jul 3:2025.06.30.662456. doi: 10.1101/2025.06.30.662456.
Alveolar type II (AT2) progenitor cell exhaustion and impaired regenerative capacity are key pathogenic hallmarks in idiopathic pulmonary fibrosis (IPF). Nicotinamide adenine dinucleotide (NAD ) functions as a central regulator of cellular energy metabolism. We have reported that downregulation of NAD -dependent sirtuin signaling contributes to the impaired progenitor function of IPF AT2s. In this study, we identified that a key NAD biosynthesis enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is significantly downregulated in IPF AT2s. NAMPT deficiency impairs AT2 renewal and enhances lung fibrosis through downregulation of SIRT7 and SOD2, which results in increased oxidative stress, mitochondrial dysfunction, induction of pathological transitional gene expression and impaired regenerative capacity to generate alveolar type I (AT1) cell required for gas exchange. Mice with deletion of Nampt in AT2s showed severely impaired AT2 renewal and increased susceptibility to bleomycin lung injury and spontaneous fibrois. Activation of NAMPT by small molecule activators promoted AT2 renewal, restored homeostasis, and reversed lung fibrosis. NAMPT activation could be a therapeutic strategy for restoring AT2 progenitor function and halting or reversing progressive pulmonary fibrosis.
肺泡II型（AT2）祖细胞耗竭和再生能力受损是特发性肺纤维化（IPF）的关键致病特征。烟酰胺腺嘌呤二核苷酸（NAD ）作为细胞能量代谢的核心调节因子。我们曾报道，NAD 依赖性沉默调节蛋白信号下调导致IPF AT2s的祖细胞功能受损。在本研究中，我们发现一种关键的NAD 生物合成酶，烟酰胺磷酸核糖转移酶（NAMPT），在IPF AT2s中显著下调。NAMPT缺乏通过下调SIRT7和SOD2损害AT2更新并加重肺纤维化，这导致氧化应激增加、线粒体功能障碍、病理性过渡基因表达诱导以及产生气体交换所需的肺泡I型（AT1）细胞的再生能力受损。AT2s中Nampt缺失的小鼠表现出严重受损的AT2更新以及对博来霉素肺损伤和自发性纤维化的易感性增加。小分子激活剂激活NAMPT可促进AT2更新、恢复稳态并逆转肺纤维化。NAMPT激活可能是恢复AT2祖细胞功能以及阻止或逆转进行性肺纤维化的一种治疗策略。
