Novel mitophagy activator TJ0113 restricts cytosolic mtDNA to suppress ZBP1-driven inflammation in acute lung injury
TL;DR
It is demonstrated that TJ0113, a novel mitophagy activator, confers protection against LPS-induced ALI by promoting mitochondrial quality control and limiting cytosolic mtDNA accumulation.
Abstract
Acute lung injury (ALI) is driven by excessive inflammation and mitochondrial dysfunction, but how mitochondrial DNA (mtDNA) release engages inflammatory signaling remains incompletely understood. Here, we demonstrate that TJ0113, a novel mitophagy activator, confers protection against LPS-induced ALI by promoting mitochondrial quality control and limiting cytosolic mtDNA accumulation. Transcriptomic and ultrastructural analyses showed that TJ0113 restored mitophagy and reduced oxidative stress. Single-cell transcriptomic profiling identified ZBP1 as the most prominently induced cytosolic nucleic acid sensor in injured lungs, revealing inflammatory alveolar macrophages as a major ZBP1-enriched population. Mechanistically, cytosolic mtDNA accumulation triggered ZBP1 activation, leading to necroptotic (MLKL) and pyroptotic (GSDMD) signaling. TJ0113 suppressed ZBP1 activation by enhancing mitophagy and reducing mtDNA release, and inhibition of mitophagy abolished its protective effects. Consistently, ZBP1 knockdown recapitulated the anti-inflammatory effects of TJ0113, as evidenced by reduced downstream inflammatory signaling and decreased cytosolic Z-NA puncta, and pharmacological mitochondrial depletion (EB) similarly attenuated the inflammatory phenotype. Our findings identify the mtDNA–ZBP1 axis as a critical link between mitochondrial dysfunction and inflammation in ALI, and position TJ0113 as a promising therapeutic candidate targeting this axis.