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.