KDM6B induces demethylation of H3K27me3 in MFN1 to modulate aberrant mitophagy in sepsis-induced acute lung injury

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Abstract
Acute lung injury (ALI) commonly occurs as a complication of sepsis, significantly increasing mortality rates in septic patients. Macrophages play a critical role in sepsis pathogenesis. KDM6B, a histone demethylase, has been reported to regulate macrophage death in ALI. In this study, we investigated the impact of KDM6B on macrophage processes during sepsis-induced ALI and elucidated the underlying molecular mechanisms. A cecal ligation and puncture (CLP)-induced septic mouse model was established to assess KDM6B's effects on lung injury severity and survival outcomes. Raw264.7 macrophages were stimulated with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) to create an in vitro cell injury model, followed by flow cytometric analysis for apoptosis detection, DCFH-DA staining for oxidative stress assessment, and western blot analysis for mitophagy evaluation. Chromatin immunoprecipitation assays were performed to determine KDM6B's regulatory effects on histone H3 lysine 27 (H3K27) methylation status in the MFN1 promoter region. Results demonstrated upregulated KDM6B expression in CLP-induced septic mouse lungs. In vitro experiments revealed that KDM6B knockdown significantly suppressed LPS/IFN-γ-induced apoptosis while promoting mitophagy in macrophages. In vivo analyses showed that KDM6B suppression attenuated lung injury severity, inflammatory responses, and improved survival rates in septic mice. Mechanistically, KDM6B knockdown increased H3K27me3 levels, reduced MFN1 expression, and increased H3K27me3 enrichment specifically at the MFN1 promoter region. These findings demonstrate that KDM6B silencing facilitates H3K27me3 modification at the MFN1 promoter to inhibit its transcription, subsequently suppressing macrophage apoptosis and promoting mitophagy, which collectively mitigates sepsis-induced ALI progression.

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