2. Academic Validation
  3. Discovery of a Selective Inhibitor of ZIP14 with Therapeutic Potential for Cancer-associated Cachexia

Discovery of a Selective Inhibitor of ZIP14 with Therapeutic Potential for Cancer-associated Cachexia

  • bioRxiv. 2025 Oct 23:2025.10.23.682519. doi: 10.1101/2025.10.23.682519.
Takafumi Hara,  Gen Tanaka,  Tomonori Tamura,  Masaomi Terajima,  Kengo Hamamura,  Yuya Yoshida,  Toru Kimura,  Yusuke Kasai,  Yuta Nakayama,  Takumi Umeyama,  Kohei Hosoi,  Ayaka Noguchi,  Yasuno Nakai,  Atsushi Hijikata,  Koji Matsukawa,  Satoru Ujihara,  Tetsuhiro Kawabe,  Hiroki Taguchi,  Hitomi Fujishiro,  Supak Jenkitkasemwong,  Kazuto Nunomura,  Bangzhong Lin,  Ayako Fukunaka,  Emi Yoshigai,  Kenji Mishima,  Shinsaku Nakagawa,  Michell D Knutson,  Hiroshi Imagawa,  Naoya Matsunaga,  Shigehiro Ohdo,  Itaru Hamachi,  Hiroyuki Sakurai,  Toshiyuki Fukada
PMID: 41278965 DOI: 10.1101/2025.10.23.682519
Abstract

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-interaction profiling, structure-activity 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. In vivo , 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.

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