Activation of the impaired NAMPT/SIRT7/SOD2 axis restores alveolar progenitor cell renewal in idiopathic pulmonary fibrosis.

Alveolar type 2 (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 previously reported that downregulation of NAD+-dependent sirtuin signaling contributes to the impaired progenitor cell function of IPF AT2 cells. In this study, we found that a key NAD+ biosynthesis enzyme, nicotinamide phosphoribosyltransferase (NAMPT), was significantly downregulated in IPF AT2 cells. NAMPT deficiency impaired AT2 renewal and enhanced lung fibrosis through downregulation of SIRT7 and SOD2, which resulted in increased oxidative stress, mitochondrial dysfunction, accumulated aberrant transitional cells, and impaired differentiation from AT2 to alveolar type 1 (AT1) cells. A mouse model with AT2-specific deletion of Nampt showed severely impaired AT2 renewal capacity and increased susceptibility to bleomycin lung injury. Activation of NAMPT by small-molecule activators promoted IPF AT2 renewal and reversed lung fibrosis in WT mice. NAMPT activation is a potentially promising therapeutic strategy for restoring AT2 progenitor cell function and halting or reversing progressive pulmonary fibrosis.