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However, the comprehensive mutational landscape and its functional relevance remain poorly defined. We aimed to characterize the genetic architecture and inflammatory mechanisms underlying BIPN in multiple myeloma (MM) patients. Whole exome sequencing (WES) was performed on peripheral blood mononuclear cells (PBMCs) from 20 newly diagnosed MM patients treated with BTZ, including eight patients who developed grade \u2265\u20092 BIPN and 12 controls without neuropathy. To functionally interpret genetic alterations, WES data were integrated with transcriptomic datasets from chemotherapy\u2010induced peripheral neuropathy models obtained from GEO databases. Enrichment analyses and molecular docking were conducted to identify key driver genes and potential BTZ\u2010protein interactions. WES identified 90,465 BIPN\u2010associated single nucleotide polymorphisms, with a distinct co\u2010mutation signature involving 33 zinc\u2010finger (ZNF) family genes. Integrative multi\u2010omics analysis yielded 100 candidate genes enriched in inflammatory response, neuronal development, synaptic organization, and MAPK\/NF\u2010\u03baB signaling pathways. Three key genes\u2014\n                    <jats:italic>CACNA1H<\/jats:italic>\n                    ,\n                    <jats:italic>CIC<\/jats:italic>\n                    , and\n                    <jats:italic>ABLIM2<\/jats:italic>\n                    \u2014were identified as potential driver genes and demonstrated direct binding affinity with BTZ in docking analyses. Notably, enrichment analyses also suggested shared molecular mechanisms between neurotoxicity and cardiotoxicity. Our findings revealed that inflammation\u2010driven neuronal dysfunction mediated by genetic susceptibility represented a central mechanism of BIPN. Integrative genomic profiling might provide a framework for personalized risk assessment and precision management of BTZ\u2010related neurotoxicity and associated organ toxicity.\n                  <\/jats:p>","DOI":"10.1002\/jat.70200","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T01:25:36Z","timestamp":1777512336000},"page":"4623-4635","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Susceptibility and Inflammatory Mechanisms in Bortezomib\u2010Induced Peripheral Neuropathy: Insights From Whole Exome Sequencing and Transcriptomic Analysis"],"prefix":"10.1002","volume":"46","author":[{"given":"JiaLin","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology and Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences  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of Hematology Shandong Provincial Hospital Affiliated to Shandong First Medical University  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Lyu","sequence":"additional","affiliation":[{"name":"Department of Hematology Shandong Provincial Hospital Affiliated to Shandong First Medical University  Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"QingDan","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Hematology, Anqiu People's Hospital Shandong Second Medical University  Weifang Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7530-2663","authenticated-orcid":false,"given":"LiLi","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Hematology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences  Jinan Shandong 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