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Through in-depth analysis of prostate cancer cohorts, we found that glutamate ionotropic receptor kainate (GRIK) family members, specifically GRIK2 and GRIK5, are highly expressed in neural lineage plastic prostate cancer cells, NEPC patient-derived xenografts (PDX), and NEPC patient samples. Their expression positively correlates with neuroendocrine markers and inversely correlates with androgen receptor (AR) activity. Additionally, functional analyses indicated that AR has a direct transcriptional inhibitory effect on GRIK2 and GRIK5, and the absence of AR signaling leads to the upregulation of GRIK2 and GRIK5. Further RNA sequencing analysis revealed that GRIK5 silencing reprograms the cellular transcriptome, resulting in significant downregulation of AR signaling and fatty acid metabolism, while simultaneously activating immune and inflammatory responses in enzalutamide-resistant prostate cancer cells. In both cell line and NEPC PDX organoid models, loss of GRIK5 impaired proliferation and clonogenic growth. Notably, GRIK5 also contributes to enzalutamide resistance. Pharmacological evaluation revealed that Pan-GRIK antagonists exhibit anti-tumor activity, although the required relatively high concentrations suggest that more potent therapeutic strategies should be developed. Collectively, this study establishes that GRIK family members play critical roles in enzalutamide resistance and NEPC progression, highlighting GRIK signaling as a potential therapeutic target for overcoming lineage plasticity in prostate cancer.<\/jats:p>","DOI":"10.3390\/ijms27135945","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T14:51:25Z","timestamp":1783003885000},"page":"5945","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Glutamate Ionotropic Kainate Receptors as Therapeutic Targets in Enzalutamide-Resistant and Neuroendocrine Prostate Cancer"],"prefix":"10.3390","volume":"27","author":[{"given":"Huan","family":"Qu","sequence":"first","affiliation":[{"name":"Department of Urologic Surgery, School of Medicine, University of California, Davis, CA 95817, 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University of California, Davis, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanpei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen C.","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Urologic Surgery, School of Medicine, University of California, Davis, CA 95817, USA"},{"name":"Davis Comprehensive Cancer Center, University of California, 4645 2nd Ave, Research III Bldg, Suite 2300C, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Dall\u2019Era","sequence":"additional","affiliation":[{"name":"Department of Urologic Surgery, School of Medicine, University of California, Davis, CA 95817, USA"},{"name":"Davis Comprehensive Cancer Center, University of California, 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