{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T08:18:26Z","timestamp":1788337106736,"version":"build-2803163510"},"reference-count":40,"publisher":"World Scientific Pub Co Pte Ltd","issue":"06","funder":[{"DOI":"10.13039\/501100004735","name":"Hunan Provincial Natural Science Foundation of China","doi-asserted-by":"crossref","award":["2025JJ80468"],"award-info":[{"award-number":["2025JJ80468"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82575067"],"award-info":[{"award-number":["82575067"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Am. J. Chin. Med."],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>Colorectal cancer (CRC) frequently develops resistance to 5-fluorouracil (5-FU)-based chemotherapy, which remains a major obstacle to successful treatment. Ginseng-containing Sijunzi Decoction (SJZD), a classical Traditional Chinese Medicine formula, has demonstrated antitumor activity; however, whether and how SJZD enhances 5-FU sensitivity remains largely unclear. In this study, SJZD-containing serum was prepared and administered to 5-FU-resistant CRC cell lines (HCT116\/5-FU and SW480\/5-FU). Chemosensitivity was evaluated using Cell Counting Kit-8 (CCK-8) and Calcein-AM\/propidium iodide (PI) staining assays, while ferroptosis was assessed by measuring oxidative stress-related indicators, including malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), and intracellular ferrous iron (Fe[Formula: see text]) levels. In addition, a BALB\/c nude mouse xenograft model was established to validate the synergistic antitumor effects of SJZD and 5-FU in\u00a0vivo. Protein\u2013protein interactions and ubiquitination were examined by co-immunoprecipitation and in\u00a0vitro ubiquitination assays. Our results demonstrated that SJZD markedly enhanced the sensitivity of resistant CRC cells to 5-FU by inhibiting cell proliferation and promoting ferroptosis both in\u00a0vitro and in\u00a0vivo. In the xenograft model, combined treatment with SJZD and 5-FU produced significantly greater reductions in tumor volume and tumor weight than treatment with 5-FU alone. Furthermore, the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively abolished the chemosensitizing effect of SJZD, indicating that ferroptosis is required for SJZD-mediated reversal of 5-FU resistance. Mechanistically, SJZD suppressed the expression of the E3 ubiquitin ligase membrane-associated ring finger protein 3 (MARCHF3), thereby inhibiting the ubiquitination and proteasomal degradation of arachidonate 15-lipoxygenase (ALOX15), a critical regulator of ferroptosis. Rescue experiments further demonstrated that ALOX15 silencing or MARCHF3 overexpression significantly attenuated SJZD-induced ferroptosis and reversed its sensitizing effect on 5-FU-resistant CRC cells. Collectively, these findings demonstrate that SJZD enhances the chemosensitivity of CRC cells to 5-FU by activating ferroptosis through regulation of the MARCHF3\/ALOX15 axis. This study provides mechanistic insight into the antitumor activity of SJZD and highlights its potential as a promising adjuvant strategy for overcoming 5-FU resistance in CRC.<\/jats:p>","DOI":"10.1142\/s0192415x26500709","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T03:31:34Z","timestamp":1787542294000},"page":"1875-1897","source":"Crossref","is-referenced-by-count":0,"title":["Ginseng-Containing Sijunzi Decoction Inhibits Colorectal Cancer Progression by Regulating MARCHF3-ALOX15-Mediated Ferroptosis"],"prefix":"10.1142","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5283-7725","authenticated-orcid":false,"given":"Yong","family":"Gao","sequence":"first","affiliation":[{"name":"Major in Traditional Chinese Medicine Surgery, Graduate School, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, P. R. 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