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Identifying novel vulnerabilities is therefore critical to advancing TNBC therapeutics. Mitochondrial metabolism has emerged as a key regulator of cancer cell survival and proliferation, with serine hydroxymethyltransferase 2 (SHMT2) playing a central role in mitochondrial one\u2010carbon metabolism by supplying one\u2010carbon units for nucleotide biosynthesis and maintaining redox homeostasis. Despite its established importance in cancer metabolism, the functional role and therapeutic potential of SHMT2 in TNBC remain underexplored. Here, we demonstrate that gambogic acid (GA), a natural product with reported anticancer properties, exerts potent and selective cytotoxicity against TNBC cells by covalently targeting SHMT2. GA binds specifically to the critical cysteine residue Cys241, inhibiting SHMT2 enzymatic activity and disrupting mitochondrial function. This leads to bioenergetic collapse, activation of the Nrf2\/HO\u20101 axis, iron overload, and induction of ferroptosis, a non\u2010apoptotic form of cell death increasingly recognized for its therapeutic potential. Our integrative chemoproteomic and mechanistic studies reveal a novel SHMT2\u2010mitochondria\u2010Nrf2\/HO\u20101\u2010ferroptosis axis driving GA's anti\u2010TNBC activity. Moreover, SHMT2 overexpression in TNBC correlates with tumor aggressiveness and poor prognosis, underscoring its role as a metabolic oncogene and promising drug target. These findings establish GA as a novel covalent SHMT2 inhibitor and provide a new framework for exploiting metabolic vulnerabilities to overcome TNBC treatment resistance.<\/jats:p>","DOI":"10.1002\/advs.202520252","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T22:21:23Z","timestamp":1782858083000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Covalent Inhibition of SHMT2 by Gambogic Acid Induces Ferroptosis Through Mitochondrial Collapse in Triple\u2010Negative Breast Cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Tong","family":"Yang","sequence":"first","affiliation":[{"name":"School of Chinese Materia Medica Tianjin University of Traditional Chinese Medicine  Tianjin China"},{"name":"State Key Laboratory of Chinese Medicine Modernization Tianjin University of Traditional Chinese Medicine  Tianjin China"},{"name":"Haihe Laboratory of Modern Chinese Medicine 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Geriatrics, Shenzhen People's Hospital, The Second Clinical Medical College Jinan University  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao\u2010di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica China Academy of Chinese Medical Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin Kwan","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital, The Second Clinical Medical College Jinan University  Shenzhen 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