A new study links fatty acid metabolism to rheumatoid arthritis treatment, revealing a natural compound that disrupts inflammation by targeting a previously overlooked enzyme.
A compound derived from a traditional medicinal plant may offer a new way to treat rheumatoid arthritis by targeting how the body processes fats rather than simply suppressing the immune system.
In a study published in Engineering, researchers examined obakulactone (OL), a natural molecule from Phellodendri cortex. They found that OL promotes the breakdown of acyl coenzyme A thioesterase 1 (ACOT1), a protein involved in fatty acid metabolism. This process occurs through the ubiquitin‒proteasome system and helps restore balance in unsaturated fatty acids, which are closely linked to inflammation.
Rheumatoid arthritis is not only driven by immune dysfunction but also by metabolic changes, including disruptions in lipid pathways. Targeting these pathways offers an alternative direction for treatment.
Experimental Model and Treatment Effects
The researchers tested OL in rats with rheumatoid arthritis induced by complete Freund’s adjuvant. The animals received daily doses of OL at low, medium, and high levels for 21 days.
Treated rats showed reduced joint swelling and improved cartilage and synovial tissue structure. The thymus and spleen, which are involved in immune regulation, also showed signs of recovery.
(b) Blocking the cell’s protein disposal system prevents this effect, confirming OL works through that pathway.
(c) OL reduces ACOT1 by marking it for destruction via the ubiquitin–proteasome system.
(d) By lowering ACOT1, OL reduces harmful fatty acids and inflammation signals, slows abnormal joint cell growth, and helps relieve joint damage in rheumatoid arthritis. Credit: Hongda Liu, Le Yang et al.
OL reduced the presence of inflammatory immune cells in joint tissue. It shifted macrophages from the proinflammatory M1 (CD86) type to the anti-inflammatory M2 (CD206) type and limited the formation of Th17 cells from CD4⁺ T cells.
Blood levels of inflammatory molecules, including IL-1β, IL-6, IL-17, and TNF-α, decreased. RA-related markers such as RF, CCP-Ab, CRP, and MMP-3 were also reduced, with stronger effects at higher doses.
Multiomics Insights and Cellular Mechanisms
Multiomics analyses showed that OL corrected abnormalities in key unsaturated fatty acids, including arachidonic acid, linoleic acid, and α-linolenic acid. These molecules influence inflammation through their role in signaling pathways.
In lab experiments, OL slowed the growth of synovial fibroblasts, triggered their programmed cell death, and reduced their release of inflammatory signals.
Binding studies confirmed that OL directly targets ACOT1, with a dissociation constant (Kd) of (6.18 ± 0.26) μmol·L⁻¹ (analyzed by microscale thermophoresis (MST)) and (6.34 ± 0.38) μmol·L⁻¹ (analyzed by surface plasmon resonance (SPR)). OL promotes the degradation of ACOT1, which lowers levels of stearoyl-CoA desaturase-1 (SCD1).
This effect disrupts signaling pathways that drive disease progression, including Janus kinase (JAK)–signal transducer and activator of transcription (STAT) and phosphoinositide 3-kinase (PI3K)–protein kinase B (AKT). As a result, inflammation and fibrosis in synovial fibroblasts are reduced.
Therapeutic Implications for Rheumatoid Arthritis
Additional experiments confirmed that ACOT1 is central to OL’s anti-inflammatory, antiproliferative, and proapoptotic effects, linking fatty acid regulation to immune signaling pathways.
Rheumatoid arthritis affects about 1% of the global population, and current treatments can have limited effectiveness and significant side effects.
These findings suggest that targeting ACOT1 and fatty acid metabolism could lead to more precise treatment strategies that address underlying disease mechanisms.
Reference: “Obakulactone Alleviates Rheumatoid Arthritis by Promotion of ACOT1 Degradation via the Ubiquitin‒Proteasome Pathway and Restoration of Unsaturated Fatty Acid Homeostasis” by Hongda Liu, Le Yang, Yu Yang, Huan Tang, Junling Ren, Hui Sun, Xin Sun, Songyuan Tang, Chong Qiu, Ye Sun, Jigang Wang, Guangli Yan, Ling Kong, Ying Han and Xijun Wang, 7 November 2025, Engineering.
DOI: 10.1016/j.eng.2025.10.029
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