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Treatment varies by tumor stage, but low survival rates are common across all stages. Due to these poor outcomes, there is a critical need for new treatment options and lead compounds, prompting an active search. Geopropolis has been identified as a source of bioactive compounds with various pharmacological activities, including anticancer effects against different types of cancer. Since stingless bees may be selective for native botanical species, the geopropolis they produce can have an unusual chemical profile. In this study, we report the antioxidant properties and anticancer potential of geopropolis extracts produced by Melipona bicolor, M. marginata, and M. mondury using 2D- and 3D- cell culture models. The chemical profile of these samples using UPLC-QTOF HRMS\/MS indicated ferreirin and dihydrokaempferide as the main flavonoids, along with cupressic acid and 15-acetoxyisocupressic acid as the most abundant diterpenoids. Interestingly, artepillin C, a main component of green propolis, was also detected. The geopropolis extracts showed good cell viability inhibition and selectivity indices in comparison to cisplatin used as an HCC treatment option. The antioxidant capacity of the geopropolis extracts was high and correlated with the cytotoxic effect against the HCC cells. Investigations into the mechanisms show the ability of the extracts to induce apoptosis and suppress the clonogenic potential of these cell lines. We also observed an inhibition of spheroid formation, viability, and morphology alterations. This is the first time the effects of geopropolis are described in a panel of HCC cell lines.<\/jats:p>","DOI":"10.3390\/antiox14020141","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T06:17:52Z","timestamp":1737699472000},"page":"141","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Brazilian Stingless Bee Geopropolis Exhibit Antioxidant Properties and Anticancer Potential Against Hepatocellular Carcinoma Cells"],"prefix":"10.3390","volume":"14","author":[{"given":"Mariana Muniz da","family":"Paz","sequence":"first","affiliation":[{"name":"Programa de P\u00f3s Gradua\u00e7\u00e3o em Ci\u00eancias Farmac\u00eauticas, Faculdade de Farm\u00e1cia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamila Marques","family":"Sette","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s Gradua\u00e7\u00e3o em Ci\u00eancias Farmac\u00eauticas, Faculdade de Farm\u00e1cia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raissa Eduardo","family":"dos Santos","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s Gradua\u00e7\u00e3o em Ci\u00eancias Farmac\u00eauticas, Faculdade de Farm\u00e1cia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana Luiza","family":"Barbosa e Vasconcelos","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s Gradua\u00e7\u00e3o em Ci\u00eancias Farmac\u00eauticas, Faculdade de Farm\u00e1cia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3149-2621","authenticated-orcid":false,"given":"Danielly C. 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