Paclitaxel neurotoxicity is triggered by epidermal EG5 dependent microtubule fasciculation and X-ROS formation

Paclitaxel neurotoxicity is triggered by epidermal EG5 dependent microtubule fasciculation and X-ROS formation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Paclitaxel neurotoxicity is triggered by epidermal EG5 dependent microtubule fasciculation and X-ROS formation Sandra Rieger, Chia-Jung Hsieh, Cirrincione Anthony, Mikaela Vlach, and 22 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5470731/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Taxanes are frontline chemotherapeutics that stabilize microtubules, induce mitotic arrest, and drive tumor remission. However, their off-target effects in healthy tissues, most notably cutaneous axon degeneration underlying chemotherapy-induced peripheral neuropathy (CIPN), remain poorly understood. Here, we show that paclitaxel induces microtubule fasciculation in epidermal keratinocytes through the mitotic kinesin Eg5, thereby initiating CIPN. Mechanistically, paclitaxel enhances Eg5-dependent fasciculation of detyrosinated (stabilized) microtubules, which constrict and breach the nuclear lamina. This deformation triggers tension-dependent NADPH oxidase-mediated nuclear ROS (X-ROS) formation upstream of mmp13 transcription, a pathway we previously demonstrated drives sensory axon degeneration. Employing a cross-species framework spanning zebrafish, mice, human skin biopsies, and a breast adenocarcinoma cell line, we uncover a conserved paclitaxel–Eg5 mechanism leading to fasciculation of stable microtubules in both healthy epidermis and cancer cells. These findings highlight the dualistic nature of paclitaxel action and underscore the challenge of preserving anticancer efficacy while preventing neurotoxic side effects. Biological sciences/Cell biology/Cytoskeleton/Microtubules Health sciences/Diseases/Neurological disorders/Peripheral neuropathies microtubules detyrosination paclitaxel Taxol peripheral neuropathy Eg5 Kif11 Kinesin-5 keratinocyte fasciculation nucleus MMP13 cell cycle C57BL zebrafish mice patient Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementarydatafileCommBio.pdf Supplemental data file Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5470731","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":502729734,"identity":"d3f7ddf7-6228-4bdc-9efa-dfee0632e3ea","order_by":0,"name":"Sandra 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