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

## TL;DR

A new curcumin-based prodrug delays rheumatoid arthritis by blocking inflammatory pathways and improving drug delivery.

## Contribution

Design and synthesis of curcumin-borneol prodrugs with enhanced bioavailability and anti-inflammatory efficacy in rheumatoid arthritis.

## Key findings

- Curcumin-borneol prodrugs improved cellular uptake and nuclear localization.
- The prodrugs inhibited MAPK/AP-1 signaling, reducing MMP9 and pro-inflammatory cytokines.
- In a rat model, the derivatives showed superior efficacy and safety compared to native curcumin.

## Abstract

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.

Illustrates the proposed mechanism through which curcumin-borneol ester derivatives ameliorate rheumatoid arthritis. The three derivatives were prepared through borneol esterification and subsequent salt modification. Owing to the superior membrane permeability and nuclear targeting capability conferred by the borneol moiety, these compounds are efficiently internalized into target cells. Intracellularly, they act synergistically to inhibit the phosphorylation of ERK and p38 within the MAPK signaling pathway, thereby downregulating the activity of the downstream transcription factor AP-1. This suppression subsequently leads to the reduced expression of matrix metalloproteinase-9 (MMP-9) and the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α. Ultimately, this cascade of events achieves therapeutic efficacy by mitigating joint inflammation and bone destruction.Illustration depicting the synthesis of curcumin derivatives from plant sources and borneol, their molecular structures, and a laboratory process, followed by investigation in a rat model with inflamed joint tissue. Molecular pathways inside a cell show signaling cascades involving RAS-GTP, Raf, MEK, ERK, and c-Fos, as well as TRAF6, IRAK1, TAK1, and p38 MAPK, leading to MMP-9 production. Inflammatory cells, synovial fibroblasts, and activated B cells are indicated in joint tissue, with arrows suggesting changes in cytokines IL-6, TNF-α, and IL-1β.

Illustrates the proposed mechanism through which curcumin-borneol ester derivatives ameliorate rheumatoid arthritis. The three derivatives were prepared through borneol esterification and subsequent salt modification. Owing to the superior membrane permeability and nuclear targeting capability conferred by the borneol moiety, these compounds are efficiently internalized into target cells. Intracellularly, they act synergistically to inhibit the phosphorylation of ERK and p38 within the MAPK signaling pathway, thereby downregulating the activity of the downstream transcription factor AP-1. This suppression subsequently leads to the reduced expression of matrix metalloproteinase-9 (MMP-9) and the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α. Ultimately, this cascade of events achieves therapeutic efficacy by mitigating joint inflammation and bone destruction.