Targeting Cellular Senescence as a Therapeutic Strategy to Attenuate Pulmonary Fibrosis Associated with Metabolic...

Metabolic dysfunction, in particular obesity and type 2 diabetes mellitus, increases susceptibility to pulmonary fibrosis via chronic inflammation, oxidative stress, and the accumulation of senescence. Senescent cells promote secretion of pro-fibrotic mediators that impair lung structure and repair. Here, we investigated whether reducing senescent cell burden using the mitochondria-targeted senolytic agent MitoTam, or weight-loss-induced improvement after bariatric surgery, can attenuate metabolic-associated pulmonary injury. In mice with diet-induced obesity, MitoTam improved glucose homeostasis, reduced adiposity, and markedly decreased senescence markers in lungs. This was accompanied by reduced inflammatory and fibrotic gene expression, diminished myofibroblast accumulation, and alleviated lung hypoxia. MitoTam also lowered senescence and expression of key pro-fibrotic factors, including GDF15, FGF2, TGFβ, and endothelin-1 (EDN1) in subcutaneous adipose tissue, indicating both direct pulmonary and systemic endocrine effects. In patients with class III obesity, laparoscopic sleeve gastrectomy induced substantial body weight loss, improved metabolic parameters, and significantly reduced adipose tissue senescence and pro-fibrotic signaling, including EDN1 expression and its level in the circulation. These findings identify cellular senescence as a modifiable driver linking metabolic dysfunction to pulmonary fibrosis and highlight mitochondria-targeted senolysis with MitoTam as a promising therapeutic approach.