Elevated SIRT3 Parkin-dependently activates cell mitophagy to ameliorate TNF-α-induced psoriasis-related phenotypes in HaCaT cells through deacetylating FOXO3a for its activation.

Sirtuin 3 (SIRT3) is reported to be closely relevant to the pathogenesis of psoriasis, but its detailed functions and molecular mechanisms have not been fully studied. Thus, this study aimed to investigate the effects and underlying mechanisms by which SIRT3 regulated the development of psoriasis. Specifically, we verified that SIRT3 was aberrantly downregulated in psoriasis-like skin tissues in mice models in vivo and TNF-α-stimulated HaCaT cells in vitro, compared to their corresponding normal counterparts. Functional experiments confirmed that upregulation of SIRT3 triggered cell mitophagy, restrained oxidative stress and inflammation, and inhibited excessive cell proliferation in the TNF-α-stimulated HaCaT cells in vitro, which were all ablated by co-treating cells with the mitophagy inhibitor 3-MA. Subsequently, the mechanism experiments uncovered that elevated SIRT3 deacetylated forkhead box class o 3A (FOXO3a) for its activation, which further activated the Parkin-dependent cell mitophagy in the HaCaT cells. Next, through performing the rescuing experiments, we validated that SIRT3 ameliorated TNF-α-induced psoriasis-associated phenotypes in the HaCaT cells via modulating the FOXO3a/Parkin signal pathway. Collectively, we concluded that SIRT3 triggered cell mitophagy through activating the FOXO3a/Parkin pathway to ameliorate TNF-α-induced psoriasis in the HaCaT cells, and this study provided evidences to support that SIRT3 could be used as important therapeutic target for the treatment of psoriasis.