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Ferroptosis, a recently identified form of programmed cell death, has been associated with various treatment\u2010resistant malignancies. This study aimed to explore the effect of Z\u2010GS\u2014a natural bioactive compound derived from myrrh\u2014on inhibiting the growth of drug\u2010resistant breast cancer cells via ferroptosis, and to elucidate its underlying molecular mechanisms. The growth of drug\u2010resistant breast cancer cells was evaluated using CCK\u20108 and EdU assays. Ferroptosis was assessed by measuring reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH)\/oxidized glutathione (GSSG) ratio, and FerroOrange fluorescence. A xenograft mouse model was established to compare tumor growth rates between transplanted and control groups. Gene screening was performed via RNA sequencing, and the involvement of the CDKN2B\/CDK2\/GCH1 pathway in Z\u2010GS\u2010induced growth inhibition was validated by Western blot analysis. Z\u2010GS significantly suppressed tumor growth both in\u00a0vitro and in\u00a0vivo. It induced ferroptosis in drug\u2010resistant breast cancer cells by promoting Fe\n                    <jats:sup>2+<\/jats:sup>\n                    accumulation, ROS generation, and MDA production, while reducing the GSH\/GSSG ratio. Mechanistically, Z\u2010GS downregulated GCH1 protein expression. Genetic knockout of CDKN2B effectively reversed these effects and, through modulation of CDK2 and p53, restored GCH1 expression. These findings indicate that Z\u2010GS upregulates CDKN2B, which in turn suppresses downstream GCH1 expression, ultimately triggering the ferroptosis pathway. Z\u2010GS mediates ferroptosis in drug\u2010resistant breast cancer cells by targeting the CDKN2B\/CDK2\/GCH1 pathway. These results highlight the potential of Z\u2010GS as a natural small\u2010molecule therapeutic candidate for overcoming chemotherapy resistance in breast cancer, providing a novel mechanistic strategy for further drug development.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70326","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T05:22:12Z","timestamp":1775712132000},"page":"3704-3721","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Z\u2010Guggulsterone Induces Ferroptosis in Chemoresistant Breast Cancer via a\n                    <scp>CDKN2B<\/scp>\n                    \u2010Mediated Suppression of\n                    <scp>GTP<\/scp>\n                    Cyclohydrolase 1"],"prefix":"10.1002","volume":"40","author":[{"given":"Zhuo\u2010Tao","family":"Yang","sequence":"first","affiliation":[{"name":"The Second Clinical Medical College Zhejiang Chinese Medical University  Zhejiang Hangzhou China"},{"name":"Department of Breast Surgery, General Surgery, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital) Hangzhou Medical College  Zhejiang Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1255-4259","authenticated-orcid":false,"given":"Jian\u2010Cheng","family":"Mou","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical College Zhejiang Chinese Medical University  Zhejiang Hangzhou China"},{"name":"Department of Breast Surgery, General Surgery, Cancer Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital) Hangzhou Medical College  Zhejiang Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei\u2010Min","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The Third Affiliated Hospital (The Affiliated Luohu Hospital) of Shenzhen University  Shenzhen 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