Adenine Nucleotide Translocases and Cellular Senescence in Idiopathic Pulmonary Fibrosis

To the Editor:

The article by Sui and colleagues recently published in the Journal is of great interest (1). The article sheds light on the crucial role of adenine nucleotide translocases (ANTs), particularly ANT1, in the pathogenesis of idiopathic pulmonary fibrosis (IPF) (2). We want to congratulate the authors for their excellent work. The authors found that ANT1 and ANT2 expression was significantly reduced in the lung tissue of patients with IPF compared with healthy control subjects and that loss of ANT1 was associated with increased senescence markers (p16, p21, and p53), exacerbated lung fibrosis, increased collagen deposition, and inflammation in mouse models of bleomycin- and asbestos-induced lung injury (1). In addition, they demonstrated that suppression of ANT1 in vitro resulted in increased senescence, altered mitochondrial function, and augmented secretion of proinflammatory molecules linked to the senescence-associated secretory phenotype in epithelial cell lines (1). Undoubtedly, these new insights into the role of ANT1 in IPF may offer potential therapeutic targets. However, we regret that the authors evaluated the role of ANTs only in lung epithelial cells. In addition to alveolar epithelial cells, several other types of lung cells, including fibroblasts, macrophages, and endothelial cells, have also been implicated in senescence-related IPF (3–5). Importantly, each cell type plays a distinct role in the fibrotic process. For example, senescent fibroblasts contribute to the disease by upregulating the expression of extracellular matrix proteins and promoting myofibroblast differentiation (5). Senescent endothelial cells contribute by stimulating endothelial–mesenchymal transition, whereas senescent macrophages contribute by enhancing the senescence-associated secretory phenotype (3, 4). Evaluating the mechanisms of senescence in all of these cell types is critical, because one of the major limitations of currently available senolytic drugs is their cell type–dependent activity (6). This variability in response to senolytic drugs may be attributable to the fact that the mechanisms of senescence differ by cell type. It may also explain why treatment with a combination of senolytic drugs exerting different mechanisms of action is more effective than treatment with a single drug (6).

In light of these novel observations reported by Sui and colleagues, the research community is strongly encouraged to expand the scope of investigations into ANTs in pulmonary fibrosis, with a specific focus on multiple lung cell types. The potential efficacy of therapeutic interventions targeting ANT loss or dysfunction appears promising, particularly if this anomaly is prevalent across all types of senescent lung cells, including lung fibroblasts and alveolar epithelial cells. A prior study discussed by the authors has shown that ANT deficiency is a viable therapeutic target in pulmonary fibrosis, underscoring the importance of further research in this area (7). Therefore, it is crucial to explore whether ANT deficiency is also linked to senescence in other cell types, especially lung fibroblasts, in IPF. Elucidating such associations would have significant translational value because understanding the role of ANTs in various cell types involved in IPF could lead to the development of more effective treatment strategies for this debilitating disease.