High mobility group box protein 1 (HMGB1) plays an important role in the pathogenesis of rheumatoid arthritis (RA), but the pathogenic mechanisms of HMGB1 in RA and the involvement of the lysosomal enzyme acid β-glucosidase 1 (GBA1) are not fully elucidated. The aim of the present study was to use HMGB1 to treat RA synovial fibroblasts (RASFs) and to examine the changes of transcriptional factors. RASFs were isolated from synovial tissues obtained from five RA patients undergoing synovectomy or joint replacement. RASFs were incubated with 100 ng/mL of HMGB1 for different periods. The changes in transcriptional factors were screened by RNA sequencing (RNA-seq) and results were confirmed by quantitative real-time PCR and western blot. The results showed that the mRNA of >60 genes in RASFs were differentially expressed after HMGB1 treatment. Among them, GBA1 was the most markedly decreased (-3.99 folds, P<0.001). These results were confirmed by qRT-PCR and western blot. The late-stage inflammatory mediator HMGB1 probably exerts its pathogenic role in RA by downregulating GBA1.