Background: Rheumatoid arthritis (RA) is a common immune-related disease worldwide, which is characterized by impaired fibroblast-like synoviocytes (FLS) proliferation and increased release of inflammatory cytokines. Unfortunately, the detailed mechanism by which miR-138-modulated rheumatoid arthritis has not been fully understood. Methods: RT-qPCR was used to examined mRNA level of various genes and western blot was utilized to probe protein level of acetylated H3, p-p62 and I kappa B alpha. For cytokines detection, we used ELISA method to measure the extracellular level of these cytokines. Bioinformatic tool and dual-luciferase reporter assay were employed to predict and confirm the downstream target of miR-138. Results: miR-138 was upregulated in serum and synovial tissues of RA patients. Moreover, Increased miR-138 was observed in LPS-treated FLS cells. HDAC4 was shown as the direct target of miR-138 and could be negatively regulated by miR-138. miR-138 and HDAC4 were involved in RA-related inflammatory cytokines release of FLS cells. Next, we revealed NF-kappa B and PGRN were significantly modulated by HDAC4 and miR-138 in an acetylation-dependent manner. More importantly, I kappa B alpha depletion and PGRN overexpression had the ability to rescue miR-138 inhibitor-attenuated inflammatory cytokines release of FLS cells. Conclusion: Here, we reveal miR-138 regulates RA-related inflammatory cytokines in rheumatoid arthritis through HDAC4/PGRN or HDAC4/NF-kappa B. Our findings uncover a new molecular mechanism implicated in rheumatoid arthritis, which may accelerate development of therapeutical strategy by targeting this mechanism. (C) 2019 Published by Elsevier Inc.