Sirtuin 6 ameliorates bleomycin‐induced pulmonary fibrosis via activation of lipid catabolism

Abstract Pulmonary fibrosis is a chronic and serious interstitial lung disease with little effective therapies currently. Our incomplete understanding of its pathogenesis remains obstacles in therapeutic developments. Sirtuin 6 (SIRT6) has been shown to mitigate multiple organic fibrosis. However, the involvement of SIRT6‐mediated metabolic regulation in pulmonary fibrosis remains unclear. Here, we demonstrated that SIRT6 was predominantly expressed in alveolar epithelial cells in human lung tissues by using a single‐cell sequencing database. We showed that SIRT6 protected against bleomycin‐induced injury of alveolar epithelial cells in vitro and pulmonary fibrosis of mice in vivo. High‐throughput sequencing revealed enriched lipid catabolism in Sirt6 overexpressed lung tissues. Mechanismly, SIRT6 ameliorates bleomycin‐induced ectopic lipotoxicity by enhancing lipid degradation, thereby increasing the energy supply and reducing the levels of lipid peroxides. Furthermore, we found that peroxisome proliferator‐activated receptor α (PPARα) was essential for SIRT6‐mediated lipid catabolism, anti‐inflammatory responses, and antifibrotic signaling. Our data suggest that targeting SIRT6‐PPARα‐mediated lipid catabolism could be a potential therapeutic strategy for diseases complicated with pulmonary fibrosis.