CISD1 suppresses COPD inflammation by recruiting ubiquitinated STING and altering macrophage metabolism

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. 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. Our previous study demonstrated that CSE downregulated CISD1 expression in macrophages. Based on this finding, we hypothesized that CISD1 might modulate STING activation and its downstream signaling pathways. Experimental validation confirmed that CISD1 downregulation indeed enhanced STING phosphorylation and activated the TBK1–IRF3–NF-KB pathway. Overexpression of CISD1 suppressed STING activation, type I interferon (IFN-b) 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-KB activation, restored antioxidant signaling, and alleviated epithelial apoptosis both in vitro and in COPD mouse models. Our results 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 CISD1-dependent innate immune checkpoint mechanistically links macrophage metabolic regulation to macrophage–epithelial crosstalk in COPD and identifies the CISD1–Ubr5–STING pathway—and daidzein restoration—as testable therapeutic hypotheses. CISD1 negatively regulates STING activation and downstream interferon signaling in macrophages. (OE-CISD1 inhibits STING activation and downstream pathway activation) CISD1 overexpression effectively reduced the upregulation of macrophage M1 polarization induced by STING. CISD1 promotes the ubiquitination and degradation of STING by recruiting Ubr5. CISD1 downregulation in macrophages leads to a decrease in daidzein metabolism, while exogenous supplementation of daidzein alleviates lung tissue damage and epithelial barrier disruption in COPD mice. Daidzein alleviates cigarette smoke-induced epithelial cell apoptosis and oxidative stress by inhibiting the activation of the NF-kB pathway.