A curcumin-borneol prodrug delays rheumatoid arthritis progression by inhibiting the activation of the MAPK/AP-1-MMP9 inflammatory axis

Rheumatoid arthritis (RA) therapy demands agents that are both effective and safe, yet many natural products with promising bioactivity, such as curcumin, face major translational challenges due to poor solubility and bioavailability. To overcome these limitations, we designed and synthesized a series of dual-functional curcumin-borneol prodrugs via a succinate ester linkage, including the parent ester (CBS), its water-soluble sodium salt (CBS-Na), and a disubstituted analog (DCBS), to enhance delivery and synergize therapeutic action. These derivatives markedly improved cellular uptake and nuclear localization, potently scavenged reactive oxygen species, and effectively suppressed the MAPK/AP-1 signaling axis by inhibiting ERK and p38 phosphorylation and c-Fos expression, leading to downregulation of matrix metalloproteinase MMP9 and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β). In a collagen-induced arthritis rat model, the derivatives demonstrated superior efficacy over native curcumin in alleviating joint inflammation and destruction, while exhibiting an excellent safety profile, thus representing a novel and promising therapeutic strategy for RA.