Volume 51, Issue 12 pp. 1596-1606
ORIGINAL ARTICLE

Defactinib inhibits FAK phosphorylation and regulates psoriasis via attenuating hyperproliferation of keratinocytes

Yuyue Zuo

Yuyue Zuo

Department of Dermatology, Wuhan No. 1 Hospital, Wuhan, Hubei, China

Hubei Province & Key Laboratory of Skin Infection and Immunity, Wuhan, Hubei, China

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Yueqi Zhang

Yueqi Zhang

Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

Hubei Provincial Engineering Research Center of Vascular Interventional Therapy, Wuhan, Hubei, China

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Zilu Qu

Zilu Qu

Department of Dermatology, Wuhan No. 1 Hospital, Wuhan, Hubei, China

Hubei Province & Key Laboratory of Skin Infection and Immunity, Wuhan, Hubei, China

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Bei Wang

Bei Wang

Department of Dermatology, Wuhan No. 1 Hospital, Wuhan, Hubei, China

Hubei Province & Key Laboratory of Skin Infection and Immunity, Wuhan, Hubei, China

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Yan Zhao

Yan Zhao

Department of Dermatology, Wuhan No. 1 Hospital, Wuhan, Hubei, China

Hubei Province & Key Laboratory of Skin Infection and Immunity, Wuhan, Hubei, China

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Lei Dai

Lei Dai

Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

Hubei Provincial Engineering Research Center of Vascular Interventional Therapy, Wuhan, Hubei, China

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Liuqing Chen

Corresponding Author

Liuqing Chen

Department of Dermatology, Wuhan No. 1 Hospital, Wuhan, Hubei, China

Hubei Province & Key Laboratory of Skin Infection and Immunity, Wuhan, Hubei, China

Correspondence

Li Xu and Liuqing Chen, Tongji Medical College, Huazhong University of Science and Technology, Wuhan No. 1 Hospital, No. 215, Zhongshan Avenue, Wuhan 430022, Hubei, China.

Email: [email protected] and [email protected]

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Li Xu

Corresponding Author

Li Xu

Department of Dermatology, Wuhan No. 1 Hospital, Wuhan, Hubei, China

Hubei Province & Key Laboratory of Skin Infection and Immunity, Wuhan, Hubei, China

Correspondence

Li Xu and Liuqing Chen, Tongji Medical College, Huazhong University of Science and Technology, Wuhan No. 1 Hospital, No. 215, Zhongshan Avenue, Wuhan 430022, Hubei, China.

Email: [email protected] and [email protected]

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First published: 25 July 2024

Yuyue Zuo and Yueqi Zhang have contributed equally to this work and shared first authorship.

Abstract

Excessive proliferation of keratinocytes is a crucial pathological risk feature of psoriasis. Focal adhesion kinase (FAK) is a non-receptor protein that primarily regulates cell proliferation and migration. However, the expression and regulatory mechanism of FAK in psoriasis remains unclear. This study aimed to investigate the regulation of FAK in psoriasis and examined the potential impact of FAK inhibitor on psoriasis. A small molecular selective FAK inhibitor, defactinib, was used to evaluate the effect of FAK on psoriasis in in vitro and in vivo functional assays. In our experiments, imiquimod (IMQ)-induced psoriasis mice and human keratinocytes cells were used to study the potential roles and mechanisms of FAK in psoriasis. FAK phosphorylation has been weakly detected in normal intact skin and is markedly elevated upon IMQ treatment. By reducing FAK phosphorylation (p-FAK), defactinib treatment could attenuate psoriasiform inflammation and epidermal hyperplasia in IMQ-treated mice compared with IMQ-induced mice treated with the vehicle. In in vitro studies, resiquimod (R848) increased (p-FAK) and promoted cell proliferation in human keratinocytes cells, while defactinib reversed this effect. Mechanistically, defactinib can alleviate the proliferation via JNK/YB1 pathway in vitro and in vivo. Defactinib significantly attenuates psoriasiform inflammation and epidermal hyperproliferation through the inhibition of the FAK-mediated axis. The downregulation of phosphorylated FAK then suppressed the activation of JNK/YB1 protein signaling pathway in psoriasis. Our work highlights targeting FAK as a potentially effective strategy for the treatment of psoriasis.

CONFLICT OF INTEREST STATEMENT

None declared.

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