| Summary: | Hair follicle stem cells (HFSCs) are crucial for maintaining cutaneous functions under various pathological conditions, including wounds. Tumour necrosis factor‐like weak inducer of apoptosis (TWEAK) interacts with its receptor, fibroblast growth factor‐inducible 14 (Fn14), and plays a role in the development and tissue repair of skin diseases. This study aims to elucidate the effects of TWEAK/Fn14 signalling on HFSCs and the associated mechanisms. The expressions of HFSC markers, including K19, integrin β1 and K15, were analysed via immunohistochemistry in normal and Fn14‐deficient mouse skin. Primary HFSCs were cultured in vitro and then treated with TWEAK or a chemokine (CXC motif) (CXCR) 4 inhibitor. The phenotype markers and secreted cytokines of HFSCs were assessed via immunofluorescence analysis, Western blotting and real‐time polymerase chain reaction. Our results showed that both Fn14 and CXCR4 were highly expressed in hair follicles. Fn14 deficiency led to a decrease in the expression levels of K19 and CD34. Exogenous TWEAK enhanced the expression of K15, K19, integrin β1, tumour necrosis factor receptor type 2 and CXCR4 in cultured HFSCs. Additionally, TWEAK induced the proliferation, migration and cytokine production in HFSCs. Furthermore, the Wnt/β‐catenin signalling pathway was upregulated in HFSCs upon TWEAK stimulation, and inhibitors of β‐catenin or CXCR4 suppressed the effects of TWEAK on the differentiation and secretory functions of HFSCs. In conclusion, TWEAK/Fn14 interaction regulates the expression of differentiation markers and secretory functions of HFSCs in vitro. Wnt/β‐catenin signalling or CXCR4 activation mediates the effects of TWEAK on HFSCs. Targeting the Fn14‐Wnt/β‐catenin‐CXCR4 signalling axis may offer a potential approach for managing HFSC‐related skin diseases, such as wounds.
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