Inhibition of hedgehog signalling attenuates <scp>UVB</scp>‐induced skin photoageing

<jats:title>Abstract</jats:title><jats:p>The hedgehog (Hh) signalling pathway regulates normal development and cell proliferation in metazoan organisms, but its aberrant activation can promote tumorigenesis and progression of a variety of aggressive human cancers including skin cancer. Despite its importance, little is known about its role in photoageing, a type of <jats:styled-content style="fixed-case">UV</jats:styled-content>‐induced skin lesions. In this study, we investigated the involvement of Hh signalling in the photoageing process as well as the use of an Hh‐regulating alkaloid compound as a novel therapeutic drug to regulate photoageing in keratinocytes. We found that <jats:styled-content style="fixed-case">UVB</jats:styled-content> induced Hh signalling by the expression of Hh ligands and Hh‐mediated transcription factors, respectively. Moreover, <jats:styled-content style="fixed-case">UVB</jats:styled-content>‐induced Hh activation relied on mitogen‐activated protein kinase (p38, <jats:styled-content style="fixed-case">ERK</jats:styled-content> and <jats:styled-content style="fixed-case">JNK</jats:styled-content>) activity and inflammatory responses (upregulation of <jats:styled-content style="fixed-case">COX</jats:styled-content>‐2, <jats:styled-content style="fixed-case">IL</jats:styled-content>‐1<jats:italic>β</jats:italic>,<jats:styled-content style="fixed-case"> IL</jats:styled-content>‐6 and <jats:styled-content style="fixed-case">TNF</jats:styled-content>‐<jats:italic>α</jats:italic>), resulting in premature senescence and photoageing <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic>. Notably, a selected Hh inhibitor, evodiamine, mediated photoageing blockade in a mouse skin model. Taken together, our findings demonstrated that Hh signalling is associated with <jats:styled-content style="fixed-case">UVB</jats:styled-content>‐induced photoageing, while pharmacological inhibition of Hh signalling significantly reduced experimental photoageing, indicating its potential for use as a therapeutic target for this disease.</jats:p>