PRDM16 attenuates pulmonary fibrosis through NuRD-mediated epigenetic remodeling in lung fibroblasts

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal fibrotic lung disease with a poor prognosis. While epigenetic regulation is increasingly recognized as a key driver of fibrogenesis, the underlying molecular mechanisms remain largely unclear. In this study, we identify PR domain-containing protein 16 (PRDM16) as a critical epigenetic repressor of profibrotic gene transcription. PRDM16 expression is significantly downregulated in lungs of IPF patients, in TGF-β1-activated fibroblasts, and in bleomycin (BLM)-induced mouse models. Functional analyses demonstrate that fibroblast-specific Prdm16 deletion promotes the progression of pulmonary fibrosis following BLM treatment. In contrast, overexpression of full-length PRDM16 or its truncated variant (PRDM16^ΔPR-ZF1) attenuates the fibroblast-to-myofibroblast transition and extracellular matrix (ECM) deposition, thereby mitigating BLM-induced fibrotic phenotypes. Mechanistically, PRDM16 binds to the promoters of TGF-β target genes and recruits the nucleosome remodeling and deacetylase (NuRD) complex to remove H3K27ac, resulting in silencing of profibrotic transcriptional programs. Collectively, our findings reveal a pivotal role for PRDM16 in maintaining epigenomic homeostasis during pulmonary fibrosis and underscore its potential as a promising therapeutic target for IPF.