Abstract Background Idiopathic pulmonary fibrosis (IPF) represents a devastating pulmonary disorder characterized by progressive extracellular matrix remodeling. While metabolic reprogramming emerges as a hallmark of fibrotic progression, the molecular connectors between upstream regulatory signals and downstream metabolic alterations remain elusive. Methods Through integrated multi-omics profiling and rigorous genetic validation, we employed AAV-mediated interventions in bleomycin-induced murine models and siRNA approaches in human lung fibroblasts. Human IPF specimens provided critical clinical correlation. Results CAMKK1 was consistently upregulated in fibrotic lungs and functionally proven to drive disease pathogenesis - its genetic ablation attenuated fibrosis while overexpression exacerbated pathology. Mechanistically, we established that NAT10-mediated ac4C modification serves as the upstream epigenetic switch that stabilizes CAMKK1 transcripts and enhances their translational efficiency. This regulatory axis required intact NAT10 catalytic activity, as demonstrated through structure-function analyses. Downstream, CAMKK1 orchestrates metabolic rewiring through AMPK-mediated activation of the SLC7A2 transporter, thereby reprogramming arginine metabolism to fuel collagen overproduction. Conclusion Our work delineates CAMKK1 as the central processor that integrates NAT10-dependent epitranscriptional signals with pathological metabolic rewiring in pulmonary fibrosis, revealing a clinically relevant target for therapeutic intervention. This abstract is funded by: None
Du et al. (Fri,) studied this question.
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