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International audience; As a first host barrier, the skin is constantly exposed to environmental insults that perturb its integrity. tight regulation of skin homeostasis is largely controlled by the aryl hydrocarbon receptor (AhR). Here, we demonstrate that Henna and its major pigment, the naphthoquinone Lawsone activate AhR, both in vitro and in vivo. In human keratinocytes and epidermis equivalents, Lawsone exposure enhances the production of late epidermal proteins, impacts keratinocyte differentiation and proliferation, and regulates skin inflammation. To determine the potential use of Lawsone for therapeutic application, we harnessed human, murine and zebrafish models. In skin regeneration models, Lawsone interferes with physiological tissue regeneration and inhibits wound healing. Conversely, in a human acute dermatitis model, topical application of a Lawsone-containing cream ameliorates skin irritation. Altogether, our study reveals how a widely used natural plant pigment is sensed by the host receptor AhR, and how the physiopathological context determines beneficial and detrimental outcomes. The skin acts as an important first barrier of the body, which is constantly exposed to diverse environmental and mechanical insults, such as pollution, infection, injury and radiation, amongst others 1. Additionally, the application of cosmetics and other agents can have a major impact on skin homeostasis 1. Among the most widely used skin dyes, are the extracts of Lawsonia inermis, commonly known as Henna 2. In traditional medicine, Henna has been widely used to treat bacterial and fungal infections, inflammation, cancer and various skin pathologies 3 , but the underlying mechanisms remain insufficiently understood. Major side effects of Henna preparations are caused by the additive para-phenylenediamine (PPD) that has been associated with allergic contact dermatitis 4,5. As natural product, Henna comprises a mixture of numerous compounds most of which are poorly characterized opeN There are amendments to this paper