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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE303021 | GEO | 2026/02/27

REPOSITORIES: GEO

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Project description:Intratracheal application of bleomycin is known to induce inflammatory and fibrotic reactions in the lung within a short period of time and histological features include infiltration of inflammatory cells, collagen deposition and obliteration of alveolar spaces. Because some of these features are found in patients with idiopathic pulmonary fibrosis (IPF), the bleomycin-induced lung fibrosis animal model is commonly used. However, exploratory treatments that were successfully used in this animal model and progressed to clinical trials lacked significant efficacy in humans. Here, the bleomycin-induced rat lung fibrosis model was studied using whole genome expression data that was collected at various time points and the relevance to human disease was evaluated through comparison with whole genome expression data from IPF patient-derived lung biopsies. The highest gene expression correlation between both species was observed in animals 7 days after bleomycin instillation. These gene expression signatures helped to identify a set of twelve novel disease-relevant translational gene markers that were able to separate IPF patients from controls. Furthermore, three Wnt/-catenin pathway-related genes that belong to this translational gene marker set showed, together with clinical diffusing capacity of the lung for carbon monoxide (DLCO) measurements, the potential to stratify IPF patients according to disease severity. Pirfenidone attenuated a subset of the translational gene markers in the bleomycin-induced fibrosis model, in particular those related to Wnt/-catenin-signaling. This novel translational gene marker panel offers improved possibilities to evaluate disease-modifying efficacy of novel therapeutic concepts in the bleomycin-induced rat lung fibrosis model and could be applied as a diagnostic and prognostic tool for IPF patient care. Comparison of bleomycin-treated and control rats after 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks and 8 weeks; 5 animals per group

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

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