{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T19:01:01Z","timestamp":1774378861642,"version":"3.50.1"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aimed to investigate the causal associations between circulating inflammatory proteins and small fiber neuropathy (SFN) by integrating Mendelian randomization (MR) analysis with experimental validation in animal models, and to explore their potential as therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A two-sample bidirectional MR analysis was conducted to evaluate the genetic causal associations between 91 inflammatory proteins and SFN. A paclitaxel-induced SFN mouse model was developed to assess behavioral changes, intraepidermal nerve fiber density, and the expression levels of key inflammatory factors in serum, dorsal root ganglia, and spinal cord. Computational drug screening using deep learning (TransformerCPI 2.0) combined with molecular docking analysis screened small-molecule candidates with high predicted interaction likelihood to target proteins.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MR analysis nominated suggestive associations of C-C motif chemokine ligand 11 (CCL11, odds ratio (OR)\u202f=\u202f1.460, 95% confidence interval (CI)\u202f=\u202f1.059\u20132.012,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.021) and interleukin 18 receptor 1 (IL18R1, OR\u202f=\u202f1.186, 95% CI\u202f=\u202f1.011\u20131.391,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.036) with increased SFN risk, whereas monocyte chemotactic protein 2 (MCP2) showed a suggestive protective association (OR\u202f=\u202f0.842, 95% CI\u202f=\u202f0.731\u20130.970,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.017). However, after Benjamini\u2013Hochberg false discovery rate correction across 91 proteins, none of these associations remained significant. In a murine model, paclitaxel administration induced mechanical hypersensitivity and resulted in a reduction of intraepidermal nerve fiber density. Elevated expression levels of CCL11, MCP2, IL18R1 in affected tissues were observed. Utilizing deep learning and molecular docking techniques, several small-molecule compounds with high binding affinity to these inflammatory targets were screened, indicating their potential as candidate compounds for future therapeutic development.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>CCL11 and IL18R1 are suggested as potential inflammatory targets in SFN. MCP2 showed discordant genetic and experimental signals, which may reflect context-dependent regulation and differences between genetically predicted long-term effects and acute injury responses. This study applies an integrative framework that integrates genetic prediction, experimental validation, and drug discovery, providing novel insights into SFN pathogenesis and generates hypotheses for future intervention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2026.1781396","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T16:00:22Z","timestamp":1774368022000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Identifying potential inflammatory therapeutic targets and drug candidates in small fiber neuropathy: integrating Mendelian randomization, experimental validation, and deep learning"],"prefix":"10.3389","volume":"20","author":[{"given":"Guangyu","family":"Cai","sequence":"first","affiliation":[{"name":"College of Anesthesia, Guizhou Medical University","place":["Guiyang, Guizhou, China"]},{"name":"Department of Anesthesiology, Guizhou Provincial People\u2019s Hospital","place":["Guiyang, Guizhou, China"]},{"name":"Center for Tissue Engineering and Stem Cell Research of Guizhou Medical University","place":["Guiyang, Guizhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiawei","family":"Zheng","sequence":"additional","affiliation":[{"name":"Guizhou University of Traditional Chinese Medicine","place":["Guiyang, Guizhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changmao","family":"Jiang","sequence":"additional","affiliation":[{"name":"College of Anesthesia, Guizhou Medical University","place":["Guiyang, Guizhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhu","family":"Wei","sequence":"additional","affiliation":[{"name":"College of Anesthesia, Guizhou Medical University","place":["Guiyang, Guizhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shichao","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Biology and Engineering, Guizhou Medical University","place":["Guiyang, Guizhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohua","family":"Zou","sequence":"additional","affiliation":[{"name":"College of Anesthesia, Guizhou Medical University","place":["Guiyang, Guizhou, China"]},{"name":"Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University","place":["Guiyang, Guizhou, China"]},{"name":"Guizhou Medical University Key Laboratory of Anesthesia and Pain Mechanism Research","place":["Guiyang, Guizhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yimin","family":"Ren","sequence":"additional","affiliation":[{"name":"College of Anesthesia, Guizhou Medical University","place":["Guiyang, Guizhou, China"]},{"name":"Center for Tissue Engineering and Stem Cell Research of Guizhou Medical University","place":["Guiyang, Guizhou, China"]},{"name":"Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University","place":["Guiyang, Guizhou, China"]},{"name":"Guizhou Medical University Key Laboratory of Anesthesia and Pain Mechanism Research","place":["Guiyang, Guizhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2487","DOI":"10.1097\/j.pain.0000000000001061","article-title":"High levels of cerebrospinal fluid chemokines point to the presence of neuroinflammation in peripheral neuropathic pain: a cross-sectional study of 2 cohorts of patients compared with healthy controls","volume":"158","author":"B\u00e4ckryd","year":"2017","journal-title":"Pain"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"117058","DOI":"10.1016\/j.jns.2020.117058","article-title":"Regenerative plasticity of intact human skin axons","volume":"417","author":"Bautista","year":"2020","journal-title":"J. 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