{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T15:44:24Z","timestamp":1776440664544,"version":"3.51.2"},"reference-count":98,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T00:00:00Z","timestamp":1762473600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NIDCR R01 DE029493"],"award-info":[{"award-number":["NIDCR R01 DE029493"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Perineural invasion (PNI), defined by cancer spreading or invading into the nerve, links to severe pain, recurrence, and poor prognosis. PNI contributes to nerve damage, Schwann cell activation, and sensory neuron dysfunction. Soluble tumor necrosis factor \u03b1 (solTNF\u03b1) binds to TNFR1 to drive inflammation and nerve injury, playing a key role in cancer progression and pain. This study, using a mouse sciatic nerve PNI model, explored whether blocking solTNF\u03b1-TNFR1 signaling via TNFR1 knockout or pharmacological inhibition by XPro1595 could reduce PNI-associated pain. Data showed that XPro1595, but not TNFR1 knockout, reduced tumor burden, alleviated mechanical allodynia, and improved muscle function and locomotion, primarily in females. Histological analysis in females showed that XPro1595 increased the number of myelin and dendritic cells while reducing axonal damage that resulted from PNI. In the tumor zone outside the nerve truck, XPro1595 reduced T cell and increased macrophage and dendritic cell numbers. Transcriptomic analysis revealed that XPro1595 in females with PNI upregulated mitochondrial, myelination, motor function, and immune regulation gene pathways while it downregulated inflammatory, extracellular matrix, and tumor progression pathways. Overall, we demonstrated that XPro1595 exhibited antitumor, neuroprotective, and analgesic properties in female mice, likely by promoting neuronal regeneration and mitochondrial function, while reducing inflammation and extracellular remodeling.<\/jats:p>","DOI":"10.3390\/cells14221749","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T10:35:31Z","timestamp":1762770931000},"page":"1749","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["TNFR1 Suppression by XPro1595 Reduces Peripheral Neuropathies Associated with Perineural Invasion in Female Mice"],"prefix":"10.3390","volume":"14","author":[{"given":"Morgan","family":"Zhang","sequence":"first","affiliation":[{"name":"Translational Research Center, New York University College of Dentistry, New York, NY 10010, USA"},{"name":"Pain Research Center, Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naijiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Translational Research Center, New York University College of Dentistry, New York, NY 10010, USA"},{"name":"Pain Research Center, Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6247-9905","authenticated-orcid":false,"given":"Kesava","family":"Asam","sequence":"additional","affiliation":[{"name":"Translational Research Center, New York University College of Dentistry, New York, NY 10010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles","family":"Meng","sequence":"additional","affiliation":[{"name":"Doctor of Dental Surgery Degree Program, New York University College of Dentistry, New York, NY 10010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bradley","family":"Aouizerat","sequence":"additional","affiliation":[{"name":"Translational Research Center, New York University College of Dentistry, New York, NY 10010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1075-5584","authenticated-orcid":false,"given":"Yi","family":"Ye","sequence":"additional","affiliation":[{"name":"Translational Research Center, New York University College of Dentistry, New York, NY 10010, USA"},{"name":"Pain Research Center, Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA"},{"name":"Department of Biomedical Engineering, Tandon School of Engineering, New York University, New York, NY 10010, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3379","DOI":"10.1002\/cncr.24396","article-title":"Perineural invasion in cancer: A review of the literature","volume":"115","author":"Liebig","year":"2009","journal-title":"Cancer"},{"key":"ref_2","first-page":"121","article-title":"Perineural invasion in head and neck cancers\u2013A review","volume":"7","author":"Frunza","year":"2014","journal-title":"J. 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