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By cross-comparison of RNA sequencing and RUNX1-CHIP sequencing data on mouse PNFs, we found that transcripts encoding the NF1-interacting p97\/valosin-containing protein (VCP) gene are overexpressed in PNFs. Co-immunoprecipitation confirmed that VCP bounded to neurofibromin. Western blot and immunostaining confirmed VCP overexpression in both mouse and human PNFs. Treatment of primary mouse PNF Schwann cells with CB-5083, a p97\/VCP inhibitor, led to accumulation of poly-ubiquitinated proteins and generation of irresolvable proteotoxic stress. Pharmacological or genetic inhibition of VCP reduced mouse PNF cell-derived sphere number, and genetic inhibition of Vcp in Schwann cell precursors decreased tumor-like lesion numbers in a cell transplantation model. In vivo treatment with CB-5083 in Nf1fl\/fl;DhhCre PNF mice significantly inhibited cell proliferation, increased cell apoptosis and reduced PNF volume. The combination with a MEK inhibitor did not increase efficacy compared to the single agent, supporting the hypothesis that VCP functions in parallel to, and may be modulated by, RAS\u2013MAPK signaling under stress or oncogenic conditions. The significant effects of VCP inhibition in this pre-clinical study suggest a potential novel therapy for patients with PNFs.<\/jats:p>","DOI":"10.3390\/cells15090848","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T12:15:07Z","timestamp":1778156107000},"page":"848","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Valosin-Containing Protein Contributes to Plexiform Neurofibroma Formation and Represents a Novel Therapeutic Target"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5567-4713","authenticated-orcid":false,"given":"Lalitha","family":"Gopalan","sequence":"first","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children\u2019s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youjin","family":"Na","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children\u2019s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Hu","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children\u2019s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Hall","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children\u2019s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, 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USA"},{"name":"Department of Pediatric Pathology, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5030-9354","authenticated-orcid":false,"given":"Nancy","family":"Ratner","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children\u2019s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA"},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5457-5358","authenticated-orcid":false,"given":"Gang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Cell Systems and Anatomy, Joe R. and Teresa Lozano Long School of Medicine, UT Health San Antonio, San 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