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Although AC has been used as an adjuvant to chemotherapy, the molecular basis by which it enhances the efficacy of 5-fluorouracil (5-FU) remains incompletely defined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The antitumor effect of AC alone and in combination with 5-FU was evaluated in a HCT116 xenograft mouse model and in CRC cell lines with different genetic backgrounds. Potential systemic toxicity was assessed using serum biochemical markers. Transcriptomic changes induced by AC were analyzed by RNA sequencing and integrated with network pharmacology and The Gene Expression Omnibus (GEO) (GSE17536, GSE17537, GSE41258, GSE20916). Key targets were validated by Western blotting and immunofluorescence. Cell viability, drug interaction, apoptosis, cell-cycle distribution and DNA damage were assessed using CCK-8 assays, Synergy Finder analysis, flow cytometry, and \u03b3-H2AX staining. Bioavailable AC-derived constituents were characterized by UPLC-QTOF-MS, and candidate active compounds were further evaluated by molecular docking, molecular dynamics simulation, cellular thermal shift assay, and functional validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>AC potentiated the antitumor efficacy of 5-FU in vivo and did not exacerbate 5-FU-associated hepatic or renal biochemical toxicity under the tested conditions. In vitro, AC-containing serum extracts inhibited CRC cell viability, induced reversible G2\/M-phase arrest, and enhanced 5-FU sensitivity in HCT116, CT26, and HCT15 cells. AC treatment caused limited early apoptosis, whereas delayed apoptosis was observed after prolonged exposure, suggesting that cell-cycle arrest represents the primary early response. RNA-seq and integrative analyses showed that AC suppressed pathways associated with DNA replication, mismatch repair, ribosome biogenesis, and cell-cycle progression. AC downregulated key regulators involved in cell-cycle control, DNA repair, and stress-survival signaling, including PLK1, CDK1, CCNB1, CDC25A, c-JUN, MSH2, BRCA1, and p-AKT. Combination treatment further increased \u03b3-H2AX accumulation and reduced cell-cycle regulatory proteins. Functional validation indicated that c-JUN overexpression partially attenuated AC-mediated 5-FU sensitization, whereas pharmacological AKT inhibition partially mimicked the sensitizing effect of AC. Among the serum-exposed constituents, Demethoxycurcumin and Kumatakenin were identified as bioavailable active compounds that partially recapitulated the effects of AC by inducing G2\/M-phase arrest and enhancing the antiproliferative activity of 5-FU. Molecular docking, molecular dynamics simulation, and CETSA supported their target engagement with cell-cycle regulators, particularly CCNB1 and CDK1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>AC enhances the therapeutic efficacy of 5-FU in CRC by weakening DNA repair-cell-cycle coordination and stress-survival signaling, thereby increasing 5-FU-induced DNA damage and promoting cell-cycle arrest. Demethoxycurcumin and Kumatakenin may represent important bioavailable contributors to this chemosensitizing effect, although the complete AC extract likely acts through multi-component and multi-target mechanisms. These findings provide mechanistic support for the use of AC as an adjunctive strategy to improve 5-FU-based chemotherapy in CRC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13020-026-01449-2","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T10:39:37Z","timestamp":1792579177000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Astragali Radix\u2013Curcumae Rhizoma synergistically potentiates 5-fluorouracil antitumor efficacy in colorectal cancer by disrupting DNA repair-cell cycle coordination"],"prefix":"10.1186","volume":"21","author":[{"given":"Shasha","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kexuan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qirui","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Decai","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiying","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,21]]},"reference":[{"issue":"3","key":"1449_CR1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","volume":"74","author":"F Bray","year":"2022","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. 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