Hdac11 promotes idiopathic pulmonary fibrosis through macrophage M2-type polarization and myofibroblast differentiation by inhibiting Parkin-dependent mitophagy

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which macrophages play a central role in driving fibrogenesis. In this study, we observed marked upregulation of histone deacetylase 11 (Hdac11) in lung tissues from IPF patients, lung organoid models, and bleomycin-induced fibrotic mouse lungs, with predominant expression in alveolar macrophages. Genetic deletion of Hdac11 or adoptive transfer of Hdac11-deficient macrophages significantly reduced fibrotic progression. Hdac11 loss impaired M2 macrophage polarization and macrophage-to-myofibroblast transition, leading to decreased myofibroblast accumulation and reduced profibrotic gene expression. Mechanistically, Hdac11 directly deacetylates Parkin at lysine 76, promoting its ubiquitination and proteasomal degradation, thereby suppressing Parkin-mediated mitophagy. Impaired mitophagy resulted in mitochondrial dysfunction that enhanced profibrotic macrophage activation. Pharmacological inhibition of Hdac11 alleviated bleomycin-induced lung fibrosis. These findings identify Hdac11 as a regulator of Parkin-dependent mitophagy in macrophages and suggest Hdac11 inhibition as a potential therapeutic strategy for IPF. Overall design: Alveolar macrophages (AMs) from C57BL/6 mice were stimulated with IL-33 (10 ng/mL) at 0, 3, 6, 12, 24, 48, 72, and 96 h — with three biological replicates at 0 and 24 h and one replicate at each other time point. In parallel, lung-derived primary fibroblasts were treated with TGF-ß1 (10 ng/mL) for 24 h. Transcriptomic profiles for all samples were generated via Illumina RNA-seq.