SIRT6 activation attenuates inflammatory-fibrogenic events, improves lung function and survival in experimental pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by excessive extracellular-matrix deposition and unalterable lung remodeling. MDL-800 is a selective small-molecule activator of sirtuin-6 (SIRT6) with emerging anti-inflammatory and antifibrotic potential. In this study, we evaluated the pharmacological efficacy and molecular mechanisms of MDL-800 using LPS or TGF-β-induced inflammatory and fibrotic models in RAW264.7 macrophages and LL29/DHLF fibroblasts, respectively, as well as a bleomycin-induced pulmonary fibrosis model in mice. Inflammatory, oxidative stress, and fibrotic responses were assessed using molecular, biochemical, histological, and lung function analyses. MDL-800 significantly attenuated LPS-induced pro-inflammatory mediator expression and oxidative stress in macrophages and suppressed TGF-β-induced profibrotic signaling and extracellular matrix gene/marker expression in fibroblasts. Safety evaluation revealed no detectable abnormalities following repeated MDL-800 administration (100 mg/kg). In mice, intratracheal bleomycin administration elicited pronounced inflammation, oxidative stress, and fibrotic remodeling, accompanied by significant body weight loss and mortality; these pathological alterations were markedly attenuated by MDL-800 treatment. Histopathological and Ashcroft scoring analyses demonstrated, reduced alveolar wall thickening, Collagen deposition, and structural distortion of lung tissue following MDL-800 administration, accompanied by significant improvements in lung compliance and airway resistance. Mechanistic studies using SIRT6 knockdown and lung tissue analyses revealed that MDL-800 exerts its antifibrotic effects through SIRT6-dependent epigenetic regulation involving modulation of histone-H3 acetylation (H3K9Ac, H3K14Ac, and H3K56Ac) and suppression of NF-κB signaling. Taken together, these results demonstrate that MDL-800 exhibits significant antifibrotic activity by modulating inflammatory, epigenetic, and profibrotic pathways, thereby highlighting its potential as a therapeutic candidate for IPF.