Novel mitophagy inducer TJ0113 alleviates pulmonary inflammation during acute lung injury

Zhengyuan LiuDanruo FangKaijun ChenLingling DongHuaqiong Huang^*Zhihua Chen^*

• Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

Acute lung injury (ALI) is a severe respiratory disease lacking effective treatments. Recent studies have highlighted mitochondrial damage as a crucial factor in the progression of ALI. Mitophagy, which facilitates the removal of damaged mitochondria, can reduce inflammatory responses. Our collaborators constructed a small molecule mitophagy inducer, TJ0113. TJ0113 has received clinical approval for Alport syndrome from both the China National Medical Products Administration and the U.S. Food and Drug Administration. Therefore, we explored the potential of TJ0113 as a novel therapeutic for ALI. We found that TJ0113 selectively induced mitophagy in damaged mitochondria. Furthermore, the PINK1-Parkin pathway was identified as a specific mitophagy pathway induced by TJ0113. In a mouse model of lipopolysaccharide (LPS)-induced ALI, intraperitoneal injection of TJ0113 significantly reduced lung inflammation and mortality rate. In vitro, TJ0113 significantly inhibited the expression of LPS-induced inflammatory cytokines in bone-marrow-derived macrophages. Finally, we found that TJ0113 inhibited LPS-induced inflammation by inducing mitophagy and inhibiting nuclear factor κB (NF-κB) and inflammasome activation. In conclusion, TJ0113 alleviates LPS-induced inflammation by inducing mitophagy and inhibiting NF-κB and inflammasome activation. Its selective action on damaged mitochondria suggests minimal side effects, positioning TJ0113 as a promising therapeutic candidate for ALI treatment.