Front Physiol. 2026 Aug 6;17:1888004. doi: 10.3389/fphys.2026.1888004. eCollection 2026.
ABSTRACT
INTRODUCTION: Neuropathic pain arises from lesions or dysfunction within the somatosensory system, leading to chronic disability and scarce effective therapies. The NAD⁺-dependent deacetylase SIRT6 participates in aging and inflammatory responses, yet its involvement in neuropathic pain has remained unexplored. Using two selective SIRT6 activators-UBCS039 and MDL-800-in 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.
METHODS: 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-1β, 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.
RESULTS: CCI markedly reduced SIRT6 mRNA and protein levels in the spinal dorsal horn (n=6 per group, P<0.001). Both UBCS039 and MDL-800 significantly elevated PWT and PWL (n=8, P<0.001), reduced TBARS content, restored SOD and GSH-Px activities (n=6, P<0.01), and suppressed IL-1β 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-including NLRP3 protein, cytokine levels, and pain thresholds-statistically indistinguishable from the untreated CCI group (P>0.05).
CONCLUSION: 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.
PMID:42625583 | PMC:PMC13489838 | DOI:10.3389/fphys.2026.1888004
