Inhibiting HDAC3 (Histone Deacetylase 3) Aberration and the Resultant Nrf2 (Nuclear Factor Erythroid-Derived 2-Related Factor-2) Repression Mitigates Pulmonary Fibrosis

Pulmonary fibrosis is a common cause of pulmonary hypertension and its development is associated with aberrant HDAC (histone deacetylase) activities and altered fibrogenic gene expressions; however, whether the epigenetic alterations causally affect pulmonary fibrosis remains poorly understood. Here, we report that HDAC3 aberration and the resultant inhibition of Nrf2 (nuclear factor erythroid-derived 2-related factor-2), a master transcription factor of antioxidative stress, contribute significantly to pulmonary fibrogenesis. HDAC3 is preferentially upregulated with concomitant Nrf2 suppression in fibrotic lungs of both idiopathic pulmonary fibrosis patients and bleomycin-treated mice. Genetic knockout of HDAC3 or Nrf2 inversely resisted or exacerbated the fibrotic pathologies, respectively, suggesting that they are crucial regulators of pulmonary fibrosis with opposite functions. Intriguingly, a HDAC3-selective inhibitor RGFP966 effectively reduced the Nrf2 suppression and normalized the fibrosis and adverse expressions of major fibrogenic proteins, Nrf2 downstream antioxidant enzymes and inflammatory cytokines. Nrf2 promoter contains a putative binding motif for FOXM1 (Forkhead box M1), a profibrotic transcriptional factor. HDAC3 and FOXM1 inducibly bound to Nrf2 promoter locus containing the motif in lung tissues of bleomycin mice, accompanied by reduced local histone3 acetylation, which were relieved by RGFP966. In cultured lung cells, bleomycin induction of Nrf2 suppression was partially attenuated by a FOXM1 inhibitor or when the FOXM1 motif was mutated; while in Nrf2 knockout mice, the antifibrotic effects of RGFP966 were largely reduced. Thus, HDAC3 aberration and its suppression of Nrf2 plays important roles in pulmonary fibrogenesis and strategies targeting HDAC3/Nrf2 axis by HDAC3 inhibition might potentially benefit patients with idiopathic pulmonary fibrosis and the related pulmonary fibrotic disorders.