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However, many cell state-specific metabolites remain in the unannotated part of metabolome. Here we identified a series of sulfur-containing metabolites that are actively produced in macrophages upon classical activation, but not in resting state or alternative activation state. Isotopic tracing, in vitro assays and genetic perturbations further revealed that they are formed from reactions between free cysteine and several important intermediates in glycolysis and TCA cycle. Upon classical activation, macrophages specifically upregulate the import of cystine via\n                  <jats:italic>Slc7a11<\/jats:italic>\n                  , supporting the production of these adducts. Their production dynamically responds to changes in central metabolism, environmental nutrient levels, and is regulated by nitric oxide. Finally, we confirmed these newly identified compounds also present in human samples, and most of them are significantly elevated in inflammatory granuloma annulare lesions. This work elucidated a previously uncharted part of metabolic network that is associated with inflammation and metabolic stress condition, which has important implications and set foundation for many future discoveries.\n                <\/jats:p>","DOI":"10.64898\/2026.03.18.712640","type":"posted-content","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T17:00:17Z","timestamp":1774026017000},"source":"Crossref","is-referenced-by-count":1,"title":["Discovery of metabolites produced by reactions between central carbon metabolites and cysteine that mark inflammatory macrophages"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8709-0667","authenticated-orcid":false,"given":"Nicholas L.","family":"Arp","sequence":"first","affiliation":[{"name":"Morgridge Institute for Research, Madison, WI"},{"name":"Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, WI"},{"name":"Medical Scientist Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicia","family":"Deng","sequence":"additional","affiliation":[{"name":"Morgridge Institute for Research, Madison, WI"},{"name":"Integrated Program in Biochemistry Graduate Program, University of Wisconsin-Madison, Madison, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4563-7569","authenticated-orcid":false,"given":"Jorgo","family":"Lika","sequence":"additional","affiliation":[{"name":"Morgridge Institute for Research, Madison, WI"},{"name":"Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, WI"},{"name":"Medical Scientist Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gretchen L.","family":"Seim","sequence":"additional","affiliation":[{"name":"Morgridge Institute for Research, Madison, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulo Falco","family":"Cobra","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Wisconsin-Madison, Madison, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Mellado","family":"Fritz","sequence":"additional","affiliation":[{"name":"Morgridge Institute for Research, Madison, WI"},{"name":"Integrated Program in Biochemistry Graduate Program, University of Wisconsin-Madison, Madison, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven V.","family":"John","sequence":"additional","affiliation":[{"name":"Morgridge Institute for Research, Madison, WI"},{"name":"Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swetha","family":"Rathinaraj","sequence":"additional","affiliation":[{"name":"Morgridge Institute for Research, Madison, WI"},{"name":"Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bridget E.","family":"Shields","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53715"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3568-3070","authenticated-orcid":false,"given":"Daniel","family":"Amador-Noguez","sequence":"additional","affiliation":[{"name":"Department of Bacteriology, University of Wisconsin-Madison, Madison, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Henzler-Wildman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Wisconsin-Madison, Madison, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5326-5358","authenticated-orcid":false,"given":"Jing","family":"Fan","sequence":"additional","affiliation":[{"name":"Morgridge Institute for Research, Madison, WI"},{"name":"Department of Biochemistry, University of Wisconsin-Madison, Madison, WI"},{"name":"Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026032311101048000_2026.03.18.712640v1.1","doi-asserted-by":"crossref","unstructured":"Peace, C. 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