A new study has revealed that obakulactone (OL), a natural triterpenoid derived from Phellodendri cortex, can have a therapeutic effect on rheumatoid arthritis (RA) by promoting degradation of acyl coenzyme A thioesterase 1 (ACOT1) and restoring homeostasis of unsaturated fatty acid levels.
Phellodendri cortex is a traditional Chinese medicine herb derived from the bark of Phellodendron amurense or P. chinense.
It is commonly used for its anti-inflammatory, antimicrobial and antioxidant properties. Key active compounds, notably berberine, help treat diarrhoea, fever, bacterial infections and inflammation.
The research, published in Engineering, highlights the molecular mechanism of OL in RA intervention and identifies ACOT1 as a potential therapeutic target, providing insights into fatty acid metabolism reprogramming as a therapeutic strategy for RA.
Why this matters
Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects approximately one per cent of the global population.
Current treatments for RA often have limited effectiveness and can cause severe side effects.
This study provides experimental evidence that OL may serve as a potential therapeutic agent for RA, paving the way for the development of new anti-RA medications.
The study
In this new research, scientists developed a rat model of rheumatoid arthritis (RA) using complete Freund's adjuvant (CFA) and treated the rats with OL at low (50 mg·kg⁻¹·d⁻¹), medium (100 mg·kg⁻¹·d⁻¹) and high (200 mg·kg⁻¹·d⁻¹) doses for 21 days.
OL significantly reduced joint swelling, restored the structure of cartilage and synovium and improved immune organ pathology.
It suppressed elevated CD3⁺ T cells and CD68⁺ macrophages in joint tissues, shifted macrophage polarisation from pro-inflammatory M1 to anti-inflammatory M2 and inhibited the differentiation of CD4⁺ T cells into Th17 cells.
OL also decreased serum levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-17, TNF-α) and RA diagnostic markers (RF, CCP-Ab, CRP, MMP-3).
Additionally, multiomics profiling revealed that OL corrected the dysregulated metabolism of unsaturated fatty acids in RA rats.
In vitro, OL inhibited the proliferation of RA synovial fibroblasts (SFs), promoted apoptosis and suppressed the secretion of inflammatory cytokines.
The researchers also identified ACOT1 as the direct target of OL. By enhancing ACOT1 degradation, OL reduced stearoyl-CoA desaturase-1 (SCD1) expression and inhibited the JAK-STAT and PI3K-AKT signalling pathways, thereby suppressing inflammation and fibrosis in SFs.
Further studies confirmed OL's anti-inflammatory, antiproliferative and pro-apoptotic effects through targeting ACOT1 and regulating the arachidonic acid pathway and related signalling pathways.