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Mast cells (MCs) regulate neuroimmune signaling implicated in CIPN, but their receptor-specific contributions remain poorly understood. In mice, oxaliplatin and paclitaxel produce robust mechanical and cold hypersensitivities that mirror CIPN pain.\n                      <jats:italic>Mas<\/jats:italic>\n                      -related G-protein-coupled receptor B2 (MrgprB2) and its human orthologue MrgprX2 are MC-restricted receptors that mediate non-IgE-mediated activation. However, whether MrgprB2 signaling differently contributes to oxaliplatin- versus paclitaxel-induced CIPN pain remains unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We employed a comparative mechanistic approach using wild-type (WT) and MrgprB2 knockout (KO) mice to define receptor-specific contributions to oxaliplatin- versus paclitaxel-induced CIPN pain. Behavioral assessments of mechanical and cold hypersensitivity were integrated with histological profiling of MC recruitment and mediator profiles. Genetic findings were validated pharmacologically with osthole, a natural MrgprB2\/X2 antagonist.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Both oxaliplatin and paclitaxel induced cutaneous MC accumulation in the hindpaw of WT mice, but they triggered distinct MC mediator-release profiles in vivo: oxaliplatin preferentially elevated tryptase, while paclitaxel was associated with greater histamine enrichment. Yet, neither drug directly activate MCs in vitro, as indicated by unchanged \u03b2-hexosaminidase release and calcium signaling. Importantly, MrgprB2 KO selectively attenuated oxaliplatin-induced tryptase upregulation and mechanical and cold hypersensitivity in vivo, without affecting paclitaxel-induced histamine changes or pain behavior. Consistently, with these genetic results, osthole selectively attenuated oxaliplatin-induced pain, but not paclitaxel-induced pain in WT mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings support a mechanistic dichotomy in CIPN pain, indicating that MrgprB2 contributes selectively to oxaliplatin-induced, but not paclitaxel-induced, CIPN in mice. More broadly, they suggest that CIPN involves mechanistically distinct neuroimmune states depending on the chemotherapeutic class and highlight MrgprB2\/X2 as a drug class-selective target for platinum-induced CIPN pain treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-08285-w","type":"journal-article","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T13:35:04Z","timestamp":1779543304000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mast cell-specific receptor MrgprB2 selectively mediates oxaliplatin-induced neuropathic pain"],"prefix":"10.1186","volume":"24","author":[{"given":"Leo C.","family":"Guan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoli","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruchita","family":"Kothari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meilian","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieru","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankit","family":"Uniyal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie Y.","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinzhong","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7843-3883","authenticated-orcid":false,"given":"Jing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,23]]},"reference":[{"key":"8285_CR1","doi-asserted-by":"publisher","unstructured":"Hershman DL, Lacchetti C, Loprinzi CL. 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