Abstract Background Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disorder characterized by persistent oxidative stress and macrophage-driven airway injury. However, the molecular mechanisms linking mitochondrial dysfunction to innate immune activation in COPD remain unclear. Methods Using a combination of in vitro and in vivo models, we investigated the role of CDGSH iron-sulfur domain-containing protein 1 (CISD1) in regulating macrophage inflammation and its crosstalk with epithelial cells. Transcriptomic, proteomic, and metabolomic analyses were performed to elucidate the molecular networks downstream of CISD1. Co-immunoprecipitation, ubiquitination assays, and confocal imaging were used to characterize the interaction between CISD1, STING, and the E3 ligase Ubr5. Results We found that cigarette smoke extract (CSE) markedly downregulated CISD1 expression in macrophages, leading to enhanced STING phosphorylation and activation of the TBK1-IRF3-NF-κB pathway. Overexpression of CISD1 suppressed STING activation, type I interferon (IFN-β) production, and pro-inflammatory cytokine expression. Mechanistically, CISD1 directly interacted with STING and recruited Ubr5 to promote K48-linked ubiquitination and proteasomal degradation of STING, thereby restraining excessive innate immune signaling. Metabolomic profiling further revealed that CISD1 deficiency reduced intracellular daidzein, a key anti-inflammatory metabolite. Supplementation with daidzein attenuated NF-κB activation, restored Nrf2-HO-1 antioxidant signaling, and alleviated epithelial apoptosis both in vitro and in COPD mouse models. Conclusion Our data support a model in which CISD1 restrains STING-dependent innate immune activation by recruiting Ubr5 to catalyze ubiquitination and proteasomal turnover of STING, thereby dampening macrophage inflammation and preserving epithelial integrity under cigarette smoke exposure. This mitochondria-to-innate-immunity checkpoint mechanistically links mitochondrial homeostasis to macrophage-epithelial crosstalk in COPD and identifies the CISD1-Ubr5-STING pathway—and daidzein restoration—as testable therapeutic hypotheses. This abstract is funded by: 无
Gao et al. (Fri,) studied this question.