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Caffeine (CAF), a widely consumed bioactive compound, has been reported to exert chemopreventive effects in HCC, but its interaction with standard therapies remains poorly explored. We investigated whether CAF enhances the antitumor effects of sorafenib (SOR) chemotherapy in preclinical HCC models. C3H\/HeJ mice were submitted to diethylnitrosamine (DEN)\u2010induced hepatocarcinogenesis and treated with CAF (50\u2009mg\/kg), SOR (30\u2009mg\/kg), or their combination for 3 weeks. C3A+LX2 spheroids and transwell co\u2010cultures were also exposed to CAF, SOR, or their combination at 1\/5 or 1\/10 of the half\u2010maximal effective concentration. The combination of CAF and SOR produced a synergistic reduction in tumor spheroid viability, consistent with the transcriptomic alterations observed, and inhibited HCC cell colony formation. Nonetheless, treatments exerted comparable effects on reducing liver tumor volume and\n                    <jats:italic>Afp<\/jats:italic>\n                    expression in vivo. Although only CAF\u2009+\u2009SOR reduced serum ALT levels and uniquely downregulated HCC\u2010related\n                    <jats:italic>Ccl3<\/jats:italic>\n                    , treatments showed differential and subtle transcriptomic impacts in DEN\u2010induced hepatocarcinogenesis, with no promoting or additive effects when combined. In summary, while CAF potentiated SOR antitumoral activity in vitro, their combination did not lead to major effects in vivo, eliciting the need for further investigation.\n                  <\/jats:p>","DOI":"10.1002\/jbt.71017","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T18:07:07Z","timestamp":1784138827000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Caffeine in the Context of Sorafenib Chemotherapy: Insights From Experimental Hepatocarcinogenesis"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3451-9754","authenticated-orcid":false,"given":"Leticia Cardoso","family":"Valente","sequence":"first","affiliation":[{"name":"Experimental Research Unit (UNIPEX), Botucatu Medical School S\u00e3o Paulo State University (UNESP) Botucatu SP Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia Stocco 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