A groundbreaking study published in the journal Engineering has revealed that a natural compound called obakulactone (OL) may offer a novel approach to treating rheumatoid arthritis (RA). OL, a tetracyclic triterpenoid isolated from Phellodendri cortex, has been found to reduce signs of arthritis by promoting the breakdown of acyl coenzyme A thioesterase 1 (ACOT1) through the ubiquitin‒proteasome pathway and by restoring the balance of unsaturated fatty acids.

How Obakulactone Works

The researchers discovered that OL binds directly to ACOT1, a protein that plays a crucial role in regulating cell survival, growth, inflammation, and fibrosis. By increasing the ubiquitination-mediated proteasomal degradation of ACOT1, OL reduces the levels of the downstream protein stearoyl-CoA desaturase-1 (SCD1). This, in turn, limits the activation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathways.

OL’s anti-inflammatory, antiproliferative, and proapoptotic effects were found to be mediated by its ability to target ACOT1, regulate the arachidonic acid pathway, and influence the downstream JAK-STAT/PI3K-AKT signaling pathways. The researchers used multiomics techniques, including metabolomics, MALDI mass spectrometry imaging, and proteomics, to examine how OL affected biological processes throughout the body.

Their analysis revealed that rheumatoid arthritis had disrupted the production and metabolism of several unsaturated fatty acids, including arachidonic acid, linoleic acid, and α-linolenic acid. OL helped correct these abnormalities, promoting the breakdown of ACOT1 and restoring the balance of unsaturated fatty acids.

Reducing Joint Swelling and Damage

The researchers tested OL in rats with rheumatoid arthritis triggered by complete Freund’s adjuvant (CFA). The animals received low (50 mg·kg-1·d-1), medium (100 mg·kg-1·d-1), and high (200 mg·kg-1·d-1) doses of OL for 21 days. Treatment significantly reduced swelling in the joints, restored the normal structure of cartilage and the synovium, and improved abnormal changes in immune organs, including the thymus and spleen.

OL also altered immune activity within the joints, reducing the unusually high levels of CD3+ T cells and CD68+ macrophages. At the same time, it shifted macrophages away from the proinflammatory M1 (CD86) state and toward the anti-inflammatory M2 (CD206) state. OL limited the development of CD4+ T cells into inflammation-promoting Th17 cells.

Blood tests showed that OL lowered several inflammatory molecules in a dose-dependent manner, including IL-1β, IL-6, IL-17, and TNF-α. The treatment also reduced rheumatoid arthritis markers, including RF, CCP-Ab, CRP, and MMP-3.

A Potential New Rheumatoid Arthritis Strategy

RA is a chronic systemic autoimmune disease that affects approximately 1% of people worldwide. It occurs when the immune system mistakenly attacks healthy joint tissue, causing pain, swelling, stiffness, and progressive damage. Existing treatments do not work equally well for everyone and can sometimes cause serious adverse effects.

The new findings provide preclinical evidence that OL could serve as a potential therapeutic compound for rheumatoid arthritis. They also highlight ACOT1 and unsaturated fatty acid metabolism as promising targets for future drug development. Further studies will be needed to determine whether OL is safe and effective in humans.