Cycloastragenol Ameliorates Psoriasis by Promoting Keratinocyte Autophagy via Modulating Subcellular Localization of ZKSCAN3

Psoriasis is a prevalent chronic skin disease. Cycloastragenol (CAG) has been shown to activate autophagy and alleviate epidermal keratinocyte hyperproliferation in psoriasis. This study aimed to clarify the mechanism of CAG‐mediated autophagy in psoriasis‐like models. We treated C57BL/6 mice with imiquimod cream and stimulated HaCaT cells with a cytokine mixture (C‐mix) to establish mouse and cell models. Psoriasis area and severity index scores were used to evaluate pathological changes. Autophagy flux was monitored using a monomeric red fluorescent protein–green fluorescent protein–microtubule‐associated protein 1 light chain 3 assay. The interaction between sirtuin 1 (SIRT1) and zinc finger containing Krüppel‐associated box and SCAN domain 3 (ZKSCAN3), as well as ZKSCAN3 acetylation, was examined using co‐immunoprecipitation. Our results found that CAG alleviated autophagy inhibition in the imiquimod‐induced psoriasis‐like mouse model and enhanced autophagy by upregulating SIRT1 expression. ZKSCAN3 inhibited autophagy in the C‐mix‐stimulated psoriasis‐like cellular model, while SIRT1 reduced the nuclear localization of ZKSCAN3 through deacetylation. ZKSCAN3 overexpression reversed SIRT1‐mediated autophagy enhancement, whereas CAG promoted autophagy by regulating the nuclear localization of ZKSCAN3. In conclusion, our findings demonstrate that CAG ameliorates autophagy inhibition by modulating the SIRT1/ZKSCAN3 axis in psoriasis.