{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T04:54:11Z","timestamp":1781585651808,"version":"3.54.5"},"reference-count":53,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T00:00:00Z","timestamp":1778371200000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Capecitabine (CAP) is an orally administered prodrug of fluorouracil, predominantly utilized in the treatment of solid tumors. Triggering tumor ferroptosis is an important mechanism for the treatment of hepatocellular carcinoma (HCC). However, the potential of CAP to induce ferroptosis in HCC, along with the underlying mechanisms, remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, a subcutaneous HCC model was constructed using the syngeneic Hepa1\u20106 cell line in C57BL\/6 mice, followed by treatment with metronomic CAP (mCAP). The anti\u2010tumor effects of mCAP were evaluated by monitoring tumor volume, performing pathological staining, and evaluating tumor oxidative stress levels. In\u00a0vitro, various thymidylate synthase (TYMS) inhibitors were used to treat both mouse and human HCC cell lines. Furthermore, TYMS\u2010overexpressing plasmids were transfected into mouse and human HCC cell lines to directly investigate their impact on intracellular oxidative stress. Intracellular oxidative stress and ferroptosis\u2010related markers were detected using flow cytometry, transmission electron microscopy, and Western blotting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      5\u2010FU, an active metabolite of CAP, as well as TYMS\u2010specific inhibitors, suppressed the proliferation of Hepa1\u20106 and HepG2 cells. These treatments promoted p67\n                      <jats:sup>phox<\/jats:sup>\n                      expression, activated nicotinamide adenine dinucleotide phosphate hydrogen oxidase (NOX), induced reactive oxygen species production, and increased ferrous ion accumulation. Electron microscopy revealed mitochondrial alterations characteristic of ferroptosis. Raltitrexed, another TYMS inhibitor, also induced ferroptosis in hepatocellular carcinoma cells. In\u00a0vivo, the anti\u2010tumor effect of mCAP was antagonized by co\u2010treatment with an NOX inhibitor.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>CAP targets TYMS to induce ferroptosis by activating NOX, thereby inhibiting HCC progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.71898","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T03:30:12Z","timestamp":1778470212000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metronomic Capecitabine Triggers Ferroptosis in Hepatocellular Carcinoma Cells Through Inhibition of\n                    <scp>TYMS<\/scp>"],"prefix":"10.1002","volume":"15","author":[{"given":"Ruining","family":"Yang","sequence":"first","affiliation":[{"name":"Nankai University School of Medicine  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