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.

SIRT3/6: an amazing challenge and opportunity in the fight against fibrosis and aging

“…Notably, peroxisome proliferator-activated receptor α (PPARα) has been identified as a critical mediator of SIRT6’s effects on lipid catabolism, anti-inflammatory response, and anti-fibrotic signaling. These findings suggest that targeting the SIRT6-PPARα-mediated lipid catabolic pathway holds promise as a potential therapeutic strategy for pulmonary fibrosis and related disorders [ 31 ]. In addition, other studies have demonstrated that SIRT6 inhibits NF-κB signaling pathway and blocks TGF-β1-induced lung myofibroblast differentiation [ 95 , 124 ].…”

Protein modifications and diseases

“…The authors also discussed the metabolic pathways producing these four-carbon acyl-CoAs which regulate lysine acylation and deacylation, and functions of these lysine acylation (Fang & Li, 2023). Another study in this special issue reported new role of SIRT6-mediated metabolic regulation in pulmonary fibrosis (He et al, 2023). He et al (2023) discovered that SIRT6 protected against bleomycin-induced injury of alveolar epithelial cells and reduced pulmonary fibrosis of mice in vivo.…”

“…Another study in this special issue reported new role of SIRT6-mediated metabolic regulation in pulmonary fibrosis (He et al, 2023). He et al (2023) discovered that SIRT6 protected against bleomycin-induced injury of alveolar epithelial cells and reduced pulmonary fibrosis of mice in vivo. SIRT6 reduced bleomycin-induced ectopic lipotoxicity by enhancing lipid degradation to increase the energy supply and decrease lipid peroxides.…”

“…Their findings suggest SIRT6-PPARα-mediated lipid catabolism as a potential therapeutic target for diseases associated with pulmonary fibrosis (He et al, 2023). This special issue also includes original research articles to identify new targets of protein SUMOylation and ubiquitination (Chen et al, 2023;Joo et al, 2023).…”

“…PPARα was essential for SIRT6‐mediated lipid catabolism. Their findings suggest SIRT6‐PPARα‐mediated lipid catabolism as a potential therapeutic target for diseases associated with pulmonary fibrosis (He et al, 2023).…”