International immunopharmacology · 2026
Mito-TEMPO attenuates LPS-induced acute lung injury accompanied by ferroptosis suppression and reduced HSP90-STING association.
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Yao Yun, Guo Wei, Tian Yujia, Zeng Lisheng, Xia Xin, Wang Zhiwei, Gao Jiasheng, Li Miaomiao, Zhang Fang, Xu Dalin
Аннотация
BACKGROUND: Acute lung injury (ALI) lacks effective pharmacological treatments. Ferroptosis and stimulator of interferon genes (STING)-dependent immune activation contribute to ALI, but whether the heat shock protein 90 (HSP90)-STING interface can be modulated to limit ferroptotic injury remains unclear. This study investigated whether Mito-TEMPO protects against lipopolysaccharide (LPS)-induced ALI in relation to the HSP90-STING-ferroptosis axis.
METHODS: LPS-induced ALI was established in wild-type and STING-deficient (STING-/-) mice with intratracheal Mito-TEMPO pretreatment. Lung injury, vascular permeability, inflammation, and ferroptosis were evaluated by histology, bronchoalveolar lavage fluid (BALF) analysis, ELISA, qRT-PCR, Western blotting, immunohistochemistry, and immunofluorescence. LPS-stimulated BEAS-2B cells were used for in vitro validation, and additional A549 cells with STING overexpression were employed to further validate STING-dependent signaling and ferroptosis-related mechanisms. Network pharmacology, molecular docking, co-immunoprecipitation, and colocalization analyses were performed to examine HSP90-STING signaling.
RESULTS: Mito-TEMPO alleviated LPS-induced pulmonary edema, inflammatory infiltration, tissue injury, BALF protein accumulation, BALF cellularity, and IL-6, IL-1β, and TNF-α expression. It also reversed ferroptosis-associated changes by restoring GPX4 and FTH1 while reducing NCOA4, PTGS2, and 4-HNE, with decreased lipid peroxidation in SFTPC+ alveolar type II (AT2) cells. Similar anti-inflammatory and anti-ferroptotic effects were observed in BEAS-2B cells. Network pharmacology and docking analyses suggested HSP90 as a potential Mito-TEMPO-associated target. Co-immunoprecipitation and immunofluorescence analyses showed reduced HSP90-STING interaction after Mito-TEMPO treatment, accompanied by decreased levels of phosphorylated TBK1 and IRF3. In STING-deficient mice, LPS-induced injury was attenuated and the additional protective effects of Mito-TEMPO were diminished. In A549 cells, STING overexpression aggravated LPS-induced inflammatory and ferroptosis-related changes and partially attenuated the protective effects of Mito-TEMPO.
CONCLUSIONS: Mito-TEMPO attenuates LPS-induced experimental ALI in association with reduced inflammation, ferroptosis-related molecular alterations, reduced HSP90-STING interaction, and attenuated downstream STING-TBK1-IRF3 signaling. These findings suggest that the HSP90-STING-ferroptosis axis may represent a mechanistically relevant pathway warranting further investigation.
METHODS: LPS-induced ALI was established in wild-type and STING-deficient (STING-/-) mice with intratracheal Mito-TEMPO pretreatment. Lung injury, vascular permeability, inflammation, and ferroptosis were evaluated by histology, bronchoalveolar lavage fluid (BALF) analysis, ELISA, qRT-PCR, Western blotting, immunohistochemistry, and immunofluorescence. LPS-stimulated BEAS-2B cells were used for in vitro validation, and additional A549 cells with STING overexpression were employed to further validate STING-dependent signaling and ferroptosis-related mechanisms. Network pharmacology, molecular docking, co-immunoprecipitation, and colocalization analyses were performed to examine HSP90-STING signaling.
RESULTS: Mito-TEMPO alleviated LPS-induced pulmonary edema, inflammatory infiltration, tissue injury, BALF protein accumulation, BALF cellularity, and IL-6, IL-1β, and TNF-α expression. It also reversed ferroptosis-associated changes by restoring GPX4 and FTH1 while reducing NCOA4, PTGS2, and 4-HNE, with decreased lipid peroxidation in SFTPC+ alveolar type II (AT2) cells. Similar anti-inflammatory and anti-ferroptotic effects were observed in BEAS-2B cells. Network pharmacology and docking analyses suggested HSP90 as a potential Mito-TEMPO-associated target. Co-immunoprecipitation and immunofluorescence analyses showed reduced HSP90-STING interaction after Mito-TEMPO treatment, accompanied by decreased levels of phosphorylated TBK1 and IRF3. In STING-deficient mice, LPS-induced injury was attenuated and the additional protective effects of Mito-TEMPO were diminished. In A549 cells, STING overexpression aggravated LPS-induced inflammatory and ferroptosis-related changes and partially attenuated the protective effects of Mito-TEMPO.
CONCLUSIONS: Mito-TEMPO attenuates LPS-induced experimental ALI in association with reduced inflammation, ferroptosis-related molecular alterations, reduced HSP90-STING interaction, and attenuated downstream STING-TBK1-IRF3 signaling. These findings suggest that the HSP90-STING-ferroptosis axis may represent a mechanistically relevant pathway warranting further investigation.