---
title: "Senescent Peripheral Fibroblasts Drive Chemotherapy-Induced Peripheral Neuropathy via MK2-Dependen"
id: "biorxiv-9-senescent-peripheral-fibroblasts-initiate-chemotherapy-induced-peripheral"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-9-senescent-peripheral-fibroblasts-initiate-chemotherapy-induced-peripheral"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.08.04.742055v1?rss=1"
published_at: "2026-08-05T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Senescent Peripheral Fibroblasts Drive Chemotherapy-Induced Peripheral Neuropathy via MK2-Dependen
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-9-senescent-peripheral-fibroblasts-initiate-chemotherapy-induced-peripheral
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.08.04.742055v1?rss=1)
- **Published At:** 2026-08-05T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Chemotherapy-induced peripheral neuropathy (**CIPN**) is a common, disabling complication of cancer treatment characterized by axonal degeneration; the initiating cellular events were previously unclear. - This preprint reports that CIPN is initiated by **senescent peripheral fibroblasts** rather than by neurons themselves, across mechanistically distinct chemotherapeutics **paclitaxel** and **cisplatin**. - Chemotherapy-induced senescence was unexpectedly restricted to peripheral fibroblasts and did not occur in neurons, and this fibroblast senescence acts upstream of neuronal **SARM1** activation. - Genetic ablation of senescent fibroblasts prevented neuropathy, and pharmacological removal of these cells both prevented neuropathy and reversed established disease, indicating senescent fibroblasts are required for both initiation and maintenance of CIPN. - Mechanistically, senescent fibroblasts promote neuropathic injury through an **MK2-dependent senescence-associated secretory phenotype (SASP)**. - Genetic or pharmacological inhibition of **MK2** suppressed the SASP, preserved peripheral innervation, and restored sensory function in the reported studies. - These findings redefine the cellular origin of CIPN and identify **MK2-dependent fibroblast senescence** as a therapeutic target for preventing and treating chemotherapy-associated neuropathy. - The report is a preprint and has not been peer-reviewed; funding sources and competing interest statements are provided in the source.
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Taylor Malachowski 1 Washington University; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Taylor%2BMalachowski%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Malachowski%20T&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ATaylor%2BMalachowski%2B) * [ORCID record for Taylor Malachowski](http://orcid.org/0000-0002-8567-2046 "Open in new tab") Ganesh Raut 1 Washington University; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Ganesh%2BRaut%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Raut%20G&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AGanesh%2BRaut%2B) * [ORCID record for Ganesh Raut](http://orcid.org/0000-0002-3918-966X "Open in new tab") Qihao Ren 1 Washington University; 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* [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Simon%2BHaroutounian%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Haroutounian%20S&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ASimon%2BHaroutounian%2B) * [ORCID record for Simon Haroutounian](http://orcid.org/0000-0003-2231-5452 "Open in new tab") Sheila Stewart 1 Washington University; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Sheila%2BStewart%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Stewart%20S&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ASheila%2BStewart%2B) * [ORCID record for Sheila Stewart](http://orcid.org/0000-0002-2260-9576 "Open in new tab") * For correspondence: sheila.stewart@wustl.edu * [Abstract](https://www.biorxiv.org/content/10.64898/2026.08.04.742055v1)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_art/node:5680440/1) * [Info/History](https://www.biorxiv.org/content/10.64898/2026.08.04.742055v1.article-info)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_info/node:5680440/1) * [Metrics](https://www.biorxiv.org/content/10.64898/2026.08.04.742055v1.article-metrics)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_metrics/node:5680440/1) * [Supplementary material](https://www.biorxiv.org/content/10.64898/2026.08.04.742055v1.supplementary-material)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_data/node:5680440/1) * [ Preview PDF](https://www.biorxiv.org/content/10.64898/2026.08.04.742055v1.full.pdf+html)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_pdf/node:5680440/1) ![Loading](https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif) ## Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating complication of cancer therapy. Although axonal degeneration defines CIPN, the initiating cellular events remain unknown. Here, we show that CIPN is initiated by senescent peripheral fibroblasts rather than by the neuron itself. Across the mechanistically distinct chemotherapeutic agents paclitaxel and cisplatin, chemotherapy-induced senescence is unexpectedly restricted to peripheral fibroblasts rather than neurons and acts upstream of neuronal SARM1 activation. Genetic or pharmacological ablation of senescent fibroblasts prevents neuropathy and reverses established disease, demonstrating that these cells are required for both disease initiation and maintenance. Mechanistically, senescent fibroblasts drive neuropathic injury through an MK2-dependent senescence-associated secretory phenotype (SASP), and genetic or pharmacological inhibition of MK2 suppresses the SASP, preserves peripheral innervation and restores sensory function. Together, these findings redefine the cellular origin of CIPN and identify MK2-dependent fibroblast senescence as a therapeutic target. ### Competing Interest Statement The authors have declared no competing interest. ## Funder Information Declared NIH, P30-AR074992, R01CA282810, R01AG093010, R01AG088264, P30 CA91842, UL1 TR000448 Department o Defense, MBC181712 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam. 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[ Download PDF](https://www.biorxiv.org/content/10.64898/2026.08.04.742055v1.full.pdf) Print/Save Options [Download PDF](https://www.biorxiv.org/content/biorxiv/early/2026/08/05/2026.08.04.742055.full.pdf)Full Text & In-line FiguresXML [More Info](https://www.biorxiv.org/about/FAQ#PrintOptions "More Information on Print/Save Options") [Supplementary Material ](https://www.biorxiv.org/content/10.64898/2026.08.04.742055v1.supplementary-material) [ Email](https://www.biorxiv.org/ "Email this Article") [ Share](https://www.biorxiv.org/) Senescent peripheral fibroblasts initiate chemotherapy-induced peripheral neuropathy Taylor Malachowski, Ganesh Raut, Qihao Ren, Radhika Mishra, Satarupa Mullick Bagchi, Dade Deavers, Xianmin Luo, Nathan Staff, Theodore J Price, Simon
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