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Many of their biological effects are mediated through redox-sensitive pathways, such as the nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant responses and cellular defense mechanisms. This study aimed to evaluate the antioxidant capacity, cytotoxicity, pro-apoptotic activity, and Nrf2-modulating effects of 22 natural product extracts traditionally used in ethnomedicine in a human leukemic K-562 cell model. The extracts were assessed for total phenolic content (TPC), radical scavenging activity (DDPH and ABTS assays), cytotoxic effects (AlamarBlue assay), apoptosis induction (caspase-3 activity), and regulation of Nrf2 target genes (<jats:italic>HO-1, NQO1<\/jats:italic> and <jats:italic>GCLC)<\/jats:italic> via RT\u2012qPCR. The extracts exhibited a wide range of antioxidant and cytotoxic activities. <jats:italic>Punica granatum, Rhodiola rosea,<\/jats:italic> and <jats:italic>Thymus vulgaris<\/jats:italic> showed high phenolic content and antioxidant potential. <jats:italic>R. rosea<\/jats:italic> displayed the most potent cytotoxic effect, whereas <jats:italic>Hypericum perforatum<\/jats:italic> induced the highest caspase-3 activity. Gene expression revealed that <jats:italic>T.vulgaris, R.rosea, Moringa oleifera, Withania somnifera, Saliva officinalis<\/jats:italic> and <jats:italic>Euphrasia officinalis<\/jats:italic> upregulated all three Nrf2 target genes, with <jats:italic>T.vulgaris<\/jats:italic> showing the greatest induction. These findings highlight the pharmacological potential of traditionally used natural products as modulators of redox signaling and apoptosis inducers in leukemia cells. The activation of the Nrf2 pathway by the selected extracts supports further investigation of their potential.<\/jats:p>","DOI":"10.1007\/s12032-025-02946-4","type":"journal-article","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T13:11:30Z","timestamp":1753967490000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Natural Nrf2 activators modulate antioxidant gene expression and apoptosis in leukemic K-562 cells"],"prefix":"10.1007","volume":"42","author":[{"given":"Iason-Spyridon","family":"Patergiannakis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia K.","family":"Georgiou-Siafis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lefkothea C.","family":"Papadopoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis S.","family":"Pappas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"2946_CR1","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1038\/nrd1657","volume":"4","author":"FE Koehn","year":"2005","unstructured":"Koehn FE, Carter GT. 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