This study identified SMYD5 as a novel regulator for synovial injury in RA, which was supported by two lines of evidence: first, the SMYD5–FoxO1 signaling axis drives FLS proliferation; second, through the SMYD5–HK2–NF-κB pathway, FLS are activated to produce numerous inflammatory mediators. Here, HK2 is linked to rheumatoid arthritis.