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These limitations underscore the need for innovative therapeutic strategies that can circumvent resistance mechanisms and enhance cancer cell cytotoxicity. Herein, we report the development of a structurally robust zinc\u2010based metal\u2013organic framework (ZnMOF) constructed from 4,4\u2032\u2010di(pyrazol\u20104\u2010yl)\u20101,1\u2032\u2010biphenyl ligands for simultaneous ferroptosis induction and chemotherapeutic delivery. Compared to the widely used ZIF\u20108, the newly developed ZnMOF exhibits superior structural stability under physiological conditions, robust doxorubicin (DOX) loading, and pH\u2010responsive drug release in acidic tumor microenvironments. In addition to efficient DOX delivery, ZnMOF effectively promotes ferroptosis by elevating intracellular reactive oxygen species, depleting glutathione, and inducing lipid peroxidation. In vivo studies using CT26 and MC38 colon carcinoma models demonstrated potent antitumor efficacy of DOX\u2010loaded ZnMOF, achieving tumor growth inhibition values of 0.91 and 0.93, respectively. These results position ZnMOF as a promising multifunctional nanoplatform for overcoming chemoresistance and enhancing therapeutic outcomes through ferroptosis\u2010based combination cancer therapy.<\/jats:p>","DOI":"10.1002\/adhm.202503611","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T06:40:16Z","timestamp":1767595216000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Doxorubicin\u2010Loaded Metal\u2013Organic Framework for Ferroptosis\u2010Enhanced Chemotherapy Through Sustained Zn Release and Glutathione Peroxidase Downregulation"],"prefix":"10.1002","volume":"15","author":[{"given":"Xin","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Chemistry The University of Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenghua","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of 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