The β-hydroxybutyrylation of Zyxin ameliorates pulmonary fibrosis by inhibiting lung fibroblast activation through the PI3K/AKT pathway

Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease with poorly understood pathogenesis. Here, we identify reduced lysine β-hydroxybutyrylation (Kbhb) of the focal adhesion protein Zyxin in bleomycin (BLM)-induced pulmonary fibrosis in mice. In a BLM-induced mouse model, we observe a significant reduction in lung tissue Kbhb levels, while β-hydroxybutyrate (β-OHB) supplementation restores Kbhb modification, there by mitigating fibrosis. Transcriptome profiling suggests that β-OHB exerts anti-fibrotic effects by modulating the PI3K/AKT pathway. Proteomic analysis further reveals a decrease in Kbhb modification at the K263 site of Zyxin in IPF mice. In vivo experiments demonstrate that Zyxin knockout or β-OHB treatment markedly alleviates fibrotic pathology and reduces collagen deposition as well as mouse mortality. This study is the first to elucidate the mechanism by which Zyxin Kbhb modification suppresses pulmonary fibrosis via the PI3K/AKT pathway, offering a novel metabolic modification-based therapeutic strategy for IPF.