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Phillygenin inhibits histone lactylation-modified NF-κB to reduce sepsis-induced acute lung injury

ABSTRACT: Acute lung injury (ALI) is a life-threatening pulmonary complication of sepsis that presents high morbidity and mortality in clinical settings and creates an urgent need for effective therapies. Phillygenin (PHI), a bioactive compound derived from Forsythia suspensa (a traditional Chinese medicinal herb), exhibits antioxidant and antitumor properties; however, its efficacy and mechanisms against sepsis-induced ALI remain largely unexplored. This study aimed to investigate the protective effects of PHI against sepsis-induced ALI by targeting H3K18 lactylation (H3K18la)/nuclear factor-κB (NF-κB)-mediated pulmonary inflammation and pyroptosis. We used a cecal ligation and puncture mouse model of septic ALI and lipopolysaccharide (LPS)-stimulated MLE12 alveolar epithelial cells for in vivo and in vitro studies. In vitro, PHI treatment downregulated nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-18 expression in LPS-stimulated MLE12 cells. PHI also suppressed the pyroptotic executors (GSDMD-N and cleaved-caspase-1) activation and reduced H3K18la levels. In vivo, PHI improved survival rates, attenuated lung histopathological damage, and ameliorated pulmonary edema in ALI mice by inhibiting H3K18la/NF-κB signaling pathway. Mechanistically, PHI attenuated inflammatory responses and pyroptosis in MLE12 cells in vitro and alleviated ALI in C57BL/6 mice by targeting the H3K18la/NF-κB pathway. These results provide novel mechanistic insights into the epigenetic regulation of septic lung injury and identify PHI as a promising therapeutic candidate for ALI.

ORGANISM(S): Mus musculus

PROVIDER: GSE315492 | GEO | 2026/01/05

REPOSITORIES: GEO

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Project description:Background: Acute Respiratory Distress Syndrome (ARDS) or its earlier stage Acute lung injury (ALI), is a worldwide health concern that jeopardizes human well-being. Currently, the treatment strategies to mitigate the incidence and mortality of ARDS are severely restricted. This limitation can be attributed, at least in part, to the substantial variations in immunity observed in individuals with this syndrome. Methods: Bulk and single cell RNA sequencing from ALI mice and single cell RNA sequencing from ARDS patients were analyzed. We utilized the Seurat program package in R and cellmarker 2.0 to cluster and annotate the data. The differential, enrichment, protein interaction, and cell-cell communication analysis were conducted. Results: The mice with ALI caused by pulmonary and extrapulmonary factors demonstrated differential expression including Clec4e, Retnlg, S100a9, Coro1a, and Lars2. We have determined that inflammatory factors have a greater significance in extrapulmonary ALI, while multiple pathways collaborate in the development of pulmonary ALI. Clustering analysis revealed significant heterogeneity in the relative abundance of immune cells in different ALI models. The autocrine action of neutrophils plays a crucial role in pulmonary ALI. Additionally, there was a significant increase in signaling intensity between B cells and M1 macrophages, NKT cells and M1 macrophages in extrapulmonary ALI. The CXCL, CSF3 and MIF, TGFβ signaling pathways play a vital role in pulmonary and extrapulmonary ALI, respectively. Moreover, the analysis of human single-cell revealed DCs signaling to monocytes and neutrophils in COVID-19-related ARDS is stronger compared to sepsis-associated ARDS. In sepsis-associated ARDS, CD8+ T and Th cells exhibit more prominent signaling to B-cell nucleated DCs. Meanwhile, both MIF and CXCL signaling pathways are specific to sepsis-associated ARDS. Conclusions: This study has identified specific gene signatures and signaling pathways in animal models and human samples that facilitate the interaction between immune cells, which could be targeted therapeutically in ARDS patients of various etiologies.

Project description:Background: Acute Respiratory Distress Syndrome (ARDS) or its earlier stage Acute lung injury (ALI), is a worldwide health concern that jeopardizes human well-being. Currently, the treatment strategies to mitigate the incidence and mortality of ARDS are severely restricted. This limitation can be attributed, at least in part, to the substantial variations in immunity observed in individuals with this syndrome. Methods: Bulk and single cell RNA sequencing from ALI mice and single cell RNA sequencing from ARDS patients were analyzed. We utilized the Seurat program package in R and cellmarker 2.0 to cluster and annotate the data. The differential, enrichment, protein interaction, and cell-cell communication analysis were conducted. Results: The mice with ALI caused by pulmonary and extrapulmonary factors demonstrated differential expression including Clec4e, Retnlg, S100a9, Coro1a, and Lars2. We have determined that inflammatory factors have a greater significance in extrapulmonary ALI, while multiple pathways collaborate in the development of pulmonary ALI. Clustering analysis revealed significant heterogeneity in the relative abundance of immune cells in different ALI models. The autocrine action of neutrophils plays a crucial role in pulmonary ALI. Additionally, there was a significant increase in signaling intensity between B cells and M1 macrophages, NKT cells and M1 macrophages in extrapulmonary ALI. The CXCL, CSF3 and MIF, TGFb signaling pathways play a vital role in pulmonary and extrapulmonary ALI, respectively. Moreover, the analysis of human single-cell revealed DCs signaling to monocytes and neutrophils in COVID-19-associated ARDS is stronger compared to sepsis-related ARDS. In sepsis-related ARDS, CD8+ T and Th cells exhibit more prominent signaling to B cell nucleated DCs. Meanwhile, both MIF and CXCL signaling pathways are specific to sepsis-related ARDS. Conclusion: This study has identified specific gene signatures and signaling pathways in animal models and human samples that facilitate the interaction between immune cells, which could be targeted therapeutically in ARDS patients of various etiologies.

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Phillygenin inhibits histone lactylation-modified NF-κB to reduce sepsis-induced acute lung injury

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