Constitutive fibroblast activation is responsible for organ
fibrosis in fibrotic disorders including
systemic sclerosis (SSc), but the underlying mechanisms are not fully understood, and effective
therapies are lacking. We investigated the expression of the mitochondrial deacetylase
sirtuin 3 (
SIRT3) and its modulation by hexafluoro, a novel fluorinated synthetic
honokiol analogue, in the context of
fibrosis. We find that augmenting cellular
SIRT3 by forced expression in normal lung and skin fibroblasts, or by hexafluoro treatment, blocked intracellular TGF-ß signaling and fibrotic responses, and mitigated the activated phenotype of SSc fibroblasts. Moreover, hexafluoro attenuated mitochondrial and cytosolic
reactive oxygen species (ROS) accumulation in TGF-β-treated fibroblasts. Remarkably, we found that the expression of
SIRT3 was significantly reduced in SSc skin biopsies and explanted fibroblasts, and was suppressed by TGF-β treatment in normal fibroblasts. Moreover, tissue levels of acetylated MnSOD, a sensitive marker of reduced
SIRT3 activity, were dramatically enhanced in lesional skin and lung biopsies from SSc patients. Mice treated with hexafluoro showed substantial attenuation of
bleomycin-induced
fibrosis in the lung and skin. Our findings reveal a cell-autonomous function for
SIRT3 in modulating fibrotic responses, and demonstrate the ability of a novel pharmacological
SIRT3 agonist to attenuate
fibrosis in vitro and in vivo. In light of the impaired expression and activity of
SIRT3 associated with organ
fibrosis in SSc, pharmacological approaches for augmenting
SIRT3 might have therapeutic potential.