{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T01:58:02Z","timestamp":1768528682869,"version":"3.49.0"},"posted":{"date-parts":[[2025,10,23]]},"group-title":"Biochemistry","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  ZIP14\/SLC39A14, a membrane-bound metal transporter, is essential for systemic metal homeostasis and has been implicated in inflammatory and metabolic disorders, including cancer-associated cachexia. Despite its biological and therapeutic significance, no selective inhibitors have been identified. Here, we identify 1-phenyl-8-(2-phenylethyl)-1,3,8-triazaspiro[4.5]decan-4-one (PPTD) as the first selective small-molecule inhibitor of ZIP14. PPTD efficiently blocks ZIP14-mediated uptake of zinc, iron, manganese, and cadmium, while sparing the closely related transporter ZIP8\/SLC39A8. Mechanistically, PPTD binds specifically to a pocket formed at the dimer interface of ZIP14, as revealed by AlphaFold3 structural prediction, ligand\u2013interaction profiling, structure\u2013activity analyses, and site-directed mutagenesis, providing direct evidence for a targeted inhibition mechanism. ZIP14-driven metal influx promotes reactive oxygen species and lipid peroxidation, leading to cytotoxicity, which PPTD effectively reverses.\n                  <jats:italic>In vivo<\/jats:italic>\n                  , PPTD ameliorates major features of cancer cachexia in mice, including weight loss, reduced survival, muscle wasting, impaired locomotor activity, and disease progression. PPTD thus provides both a chemical probe to dissect ZIP14 function and a potential therapeutic candidate for cancer cachexia, establishing a foundation for the development of therapies targeting ZIP14-mediated metal dysregulation.\n                <\/jats:p>","DOI":"10.1101\/2025.10.23.682519","type":"posted-content","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T03:30:15Z","timestamp":1761276615000},"source":"Crossref","is-referenced-by-count":0,"title":["Discovery of a Selective Inhibitor of ZIP14 with Therapeutic Potential for Cancer-associated 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