| Summary: | <i>Sideritis perfoliata</i> L. subsp. <i>perfoliata</i> is an endemic species of the Eastern Mediterranean region with several uses in traditional medicine. The present study aims to explore the unknown properties of <i>S. perfoliata</i> investigating the nutritional content as well as the antioxidant, anticancer, antituberculosis, antiwrinkle, anti-acne, hyper/hypo-pigmentation and antibacterial activities. Mineral content, nutritional value, the composition and antioxidant properties of the essential oil, the antityrosinase, the antibacterial activity and anti-elastase potential of the extract, were evaluated. The antiproliferative activity of <i>S. perfoliata</i> against cervical cancer (HeLa), human melanoma (UCT-Mel-1), human hepatocellular carcinoma (HepG2) and human epidermoid carcinoma (A431) was investigated. Cytotoxic effects on normal human keratinocyte (HaCat) and kidney epithelial (Vero) cell lines were also determined. <i>Sideritis perfoliata</i> exhibited high nutritional value of proteins and minerals (K, P, Mg, Fe, Zn, Cu). The most abundant components of the essential oil were found to be α-pinene, β-phelladrene, valeranone, β-pinene and sabinene. The ethanolic extract of <i>S. perfoliata</i> displayed moderate antioxidant potential and antibacterial activity against <i>Prevotella intermedia.</i> Noteworthy elastase and moderate anticancer potential against the human liver cancer cell line (HepG2) was observed with IC<sub>50</sub> values of 57.18 ± 3.22 μg/mL and 64.27 ± 2.04 μg/mL respectively. The noteworthy <i>in vitro</i> activity of <i>S. perfoliata</i> could be due to the presence of flavonoids and phenols in the leaves, having high nutritional value. <i>Sideritis perfoliata</i> could potentially be useful to reduce the appearance of wrinkles and for the treatment of liver cancer. The moderate antibacterial, antioxidant and elastase activity of the plant can be linked to the traditional use of <i>S. perfoliata</i> for the treatment of wounds and inflammation.
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