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Background.Bortezomib(BTZ)is the frontline chemotherapeutic drug for multiple myeloma.However,BTZ carries a severeside effect of painful chemotherapy-induced peripheral neuropathy(CIPN),which severely affects basic activities indaily life of patients.With the current lack of the pathogenic mechanism in BTZ CIPN,there are no well-established treatments to prevent or minimize this side effect,which hampered the widespread clinical use of BTZ.Methods.MaleSprague Dawley rats(220–250g)and STAT3 flox/flox mice(ID: 016923)were used.Von Frey test was performed to evaluate the pain behavior after the administration of BTZ treatment.Realtime polymerase chain reaction was used to measure the expression of mRNA.Western blot showed the expression amount of protein.Immunohistochemistry revealed the location of the protein,and ChIP analysis were performed to explore the potential binding sites between transcription factor and promoter.Results.Behavioral test showed that the administration of BTZ significantly induce peripheral neuropathy in rats.Immunohistochemistry results showed that the expression of nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 1(nlrp1)was exclusively located in IB4 and NF200 positive dorsal root ganglion(DRG)neurons.In addition,we also found that systemic administration of BTZ for consecutive 5 days significantly induced the activation of signal transducer and activator of transcription 3(STAT3)in DRG neurons of rats.Inhibition of STAT3 activity by S3I-201 reducedthe upregulation of nlrp1 mRNA and protein levels in DRG and mechanical allodynia induced by BTZ treatment.Furthermore,local knockdown of STAT3 by injection of AAV-Cre-GFP in STAT3flox/flox mice significantly decreased BTZ-induced upregulation of nlrp1 protein in DRG.Immunohistochemistry results also revealed that the expression of p-STAT3 were colocalized with nlrp1-positive cells in DRG.In addition,theresults of ChIP assay in vivo indicated that p-STAT3 might be essential forBTZ-induced nlrp1 upregulation via binding directly to the specific position of the nlrp1 promoter.In addition,western blot results demonstrated that the global acetylation of histone(H3)and histone4(H4)was significantly upregulated in DRG following BTZ treatment.ChIP analysis further indicated that the level of H3 and H4 acetylation on the nlrp1 gene promoter were increased after BTZ treatment.Inhibition of the STAT3 activity or local knockdown of STAT3 also significantly reduced the upregulated H3 and H4 acetylation induced by BTZ treatment.Conclusions.Our results suggest that BTZ treatment induces upregulation of nlrp1 in DRG via activating STAT3 and enhancing the binding of STAT3 with nlrp1 genepromoter and the H3 and H4 acetylation at thenlrp1 gene promoter,thus contributes to the painful peripheral neuropathy.