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.

Products