Lactate-associated H3K18 lactylation is involved in IGF2BP2-mediated MARCKSL1 mRNA stabilization and inflammatory signaling in LPS-induced acute lung injury.
TL;DR
The findings decipher a novel H3K18la/IGF2BP2/MARCKSL1 signaling cascade that integrates metabolic reprogramming with m6A epitranscriptomics in ALI, highlighting IGF2BP2 as a promising target for preventive intervention in airway epithelial inflammation.
Abstract
N6-methyladenosine (m6A) RNA modification regulates pulmonary inflammation, yet the precise function of the m6A reader IGF2BP2 in acute lung injury (ALI) remains elusive. Here, we reveal that IGF2BP2 and global m6A levels are significantly upregulated in lipopolysaccharide (LPS)-induced ALI. Prophylactic genetic silencing or pharmacological inhibition of IGF2BP2 robustly mitigated pulmonary hyperinflammation, epithelial apoptosis, and pathological tissue damage. Mechanistically, transcriptome profiling identified MARCKSL1 as a direct downstream target. We demonstrate that IGF2BP2 binds and post-transcriptionally stabilizes MARCKSL1 mRNA in a partially METTL3/m6A-dependent manner. Elevated MARCKSL1 subsequently drives NF-κB p65 nuclear translocation and activation, fueling the inflammatory cascade. Strikingly, we trace this IGF2BP2 dysregulation upstream to inflammatory metabolic reprogramming: elevated alveolar glycolysis drives lactate accumulation, which triggers EP300-mediated histone lactylation (H3K18la) at the IGF2BP2 promoter to activate its transcription. Pharmacological manipulation of glycolysis confirmed this metabolic-epigenetic coupling. Collectively, our findings decipher a novel H3K18la/IGF2BP2/MARCKSL1 signaling cascade that integrates metabolic reprogramming with m6A epitranscriptomics in ALI, highlighting IGF2BP2 as a promising target for preventive intervention in airway epithelial inflammation.