The Thyroid Hormone Analog GC‐1 Mitigates Acute Lung Injury by Inhibiting M1 Macrophage Polarization

Abstract Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life‐threatening condition with a high mortality rate of ≈40%. Thyroid hormones (THs) play crucial roles in maintaining homeostasis of the cellular microenvironment under stress. The previous studies confirmed that the clinical‐stage TH analog GC‐1 significantly alleviates pulmonary fibrosis by improving the function of mitochondria in epithelial cells. However, the effects of GC‐1 on macrophages in lung injury and the related mechanisms remain unclear. This study evaluated the therapeutic effects of GC‐1 in two murine models of lipopolysaccharide (LPS)‐ or hydrochloric acid (HCl)‐induced ALI. Additionally, mouse alveolar macrophages (AMs) and human THP‐1‐derived macrophages are utilized to investigate the impact of GC‐1 on macrophage polarization. GC‐1 effectively reduces the inflammatory response and lung injury in ALI mice, as evidenced by neutrophil infiltration, cytokine levels, alveolar fluid clearance, and pulmonary pathology. Notably, GC‐1 selectively inhibits M1 macrophage polarization, which may be achieved by impeding NF‐κB signaling activation through the DNMT3b‐PPARγ‐NF‐κB pathway in a TH receptor β1 (TRβ1)‐dependent manner, consequently suppressing the polarization of macrophages toward the M1 phenotype and overproduction of inflammatory cytokines. Overall, these findings highlight the immunomodulatory property of GC‐1 as an anti‐inflammatory strategy for ALI/ARDS and inflammation‐related diseases.