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Leu-F irreversibly binds to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a cross-kingdom glycolytic enzyme and a promising therapeutic target in autoimmune diseases. Crystal structure of the GAPDH\u2013leu-F complex reveals the formation of a covalent bond between leu-F and the Cys\n            <jats:sup>152<\/jats:sup>\n            residue. Leu-F notably attenuated glycolysis and concurrently diminished GAPDH-mediated stabilization of activated protein kinase B (AKT). Both leu-F and the total sesterterpenoid extract of\n            <jats:italic>Leucosceptrum canum<\/jats:italic>\n            demonstrated notable therapeutic efficacy and safety in mouse models of psoriasis and experimental autoimmune encephalomyelitis. This study underscores leu-F as a promising lead compound for autoimmune disease treatment and provides a compelling example of drug discovery inspired by chemical ecology.\n          <\/jats:p>","DOI":"10.1126\/sciadv.adw2578","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T17:58:38Z","timestamp":1753466318000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":7,"title":["Plant defense-directed discovery of a natural anti-psoriasis agent targeting GAPDH"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2039-9423","authenticated-orcid":true,"given":"Ting-Ting","family":"Zhou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Phytochemistry and Natural Medicines, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, P. R. 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