{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T13:09:00Z","timestamp":1788872940187,"version":"build-2803163510"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"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. Physiol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Neuropathic pain arises from lesions or dysfunction within the somatosensory system, leading to chronic disability and scarce effective therapies. The NAD\u207a-dependent deacetylase SIRT6 participates in aging and inflammatory responses, yet its involvement in neuropathic pain has remained unexplored. Using two selective SIRT6 activators\u2014UBCS039 and MDL-800\u2014in a rat model of chronic constriction injury (CCI), we asked whether pharmacological SIRT6 activation could ameliorate pain behaviors and, if so, through what molecular route.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>CCI surgery was performed in male Sprague-Dawley rats, and SIRT6 expression in the spinal dorsal horn was assessed post-operatively. From day 3 to day 9 after injury, rats received daily intraperitoneal injections of UBCS039 (20 mg\/kg) or MDL-800 (10 mg\/kg). On day 10, paw withdrawal thresholds (PWT) and paw withdrawal latencies (PWL) were measured. Spinal cord tissues were harvested for assessment of oxidative stress markers (TBARS, SOD, GSH-Px), pro-inflammatory cytokines (IL-1\u03b2, IL-18), NLRP3 inflammasome components (NLRP3, ASC, cleaved caspase-1), and Nrf2\/HO-1 protein levels. An additional cohort received the Nrf2 inhibitor ML385 (30 mg\/kg) 30 minutes before each MDL-800 dose to verify pathway specificity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>CCI markedly reduced SIRT6 mRNA and protein levels in the spinal dorsal horn (n=6 per group, P&amp;lt;0.001). Both UBCS039 and MDL-800 significantly elevated PWT and PWL (n=8, P&amp;lt;0.001), reduced TBARS content, restored SOD and GSH-Px activities (n=6, P&amp;lt;0.01), and suppressed IL-1\u03b2 and IL-18 production at both transcript and protein levels. Western blotting revealed that SIRT6 activation inhibited NLRP3, ASC, and cleaved caspase-1 expression while reversing the CCI-induced decline of Nrf2 and HO-1. Co-administration of ML385 abolished these protective effects, rendering all measured parameters\u2014including NLRP3 protein, cytokine levels, and pain thresholds\u2014statistically indistinguishable from the untreated CCI group (P&amp;gt;0.05).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Activating SIRT6 dampens neuropathic pain and NLRP3 inflammasome activation by restoring Nrf2 signaling. This positions SIRT6 as a previously unrecognized therapeutic target for neuropathic pain.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphys.2026.1888004","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T04:25:38Z","timestamp":1785990338000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["SIRT6 activation relieves neuropathic pain by restoring Nrf2 signaling and inhibiting NLRP3 inflammasome"],"prefix":"10.3389","volume":"17","author":[{"given":"Xintong","family":"Hao","sequence":"first","affiliation":[{"name":"Wuhan No 1 Hospital","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junkang","family":"Leng","sequence":"additional","affiliation":[{"name":"General Hospital of The Yangtze River Shipping, Wuhan Brain Hospital","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjun","family":"Tan","sequence":"additional","affiliation":[{"name":"General Hospital of The Yangtze River Shipping, Wuhan Brain Hospital","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/ph18111723","article-title":"Sirtuins as therapeutic targets for treating cancer, metabolic diseases, and neurodegenerative diseases","volume":"18","author":"Akantibila","year":"2025","journal-title":"Pharm. 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