S100A11 regulates microglial inflammatory response in neuropathic pain via H3K27ac-TFEB-mitochondrial autophagy axis.

Neuropathic pain (NP) is tightly linked to spinal microglial overactivation, sustained neuroinflammation; however, the key molecular regulators and epigenetic circuitry driving microglial functional dyshomeostasis remain incompletely defined. S100 calcium-binding protein A11 (S100A11) emerged as one of the most upregulated gene in activated spinal microglia via RNA sequencing. Here, we investigate the functional contribution of S100A11 to microglial dysfunction during NP and delineate the underlying molecular-epigenetic circuitry linking S100A11 to autophagic modulation. Using a chronic constriction injury (CCI)-induced NP mouse model, in vivo transcriptomics combined with in vitro validation demonstrated that S100A11 is markedly upregulated in activated microglia across both in vivo and in vitro NP-relevant contexts. Functionally, microglia-targeted S100A11 knockdown alleviates mechanical or thermal hyperalgesia in CCI mice, mitigates spinal synaptic damage, and concurrently suppresses microglial pyroptosis and proinflammatory cytokine release, while enhance autophagic flux in vitro. Mechanistically, S100A11 silencing promotes nuclear translocation of transcription factor EB (TFEB). To resolve the specific epigenetic modifications driving this effect, we screened key histone acetylation sites and identified histone H3 lysine 27 acetylation (H3K27ac) as the critical target: S100A11 depletion specifically elevates H3K27ac enrichment at the promoter regions of autophagy-associated genes. This H3K27ac-mediated chromatin relaxation facilitates TFEB binding to these promoters. This interaction directly drives the transcriptional activation of autophagy machinery, restoring microglial homeostasis. Collectively, our study uncovers a novel S100A11-TFEB-H3K27ac-autophagy regulatory axis that dictates microglial functional fate in NP. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10194-026-02328-9.