New research published in engineering Ovaclactone (OL) was revealed to be a natural tetracyclic triterpenoid. yellow leafy cortexexerts therapeutic effects on rheumatoid arthritis (RA) by promoting the degradation of acyl-coenzyme A thioesterase 1 (ACOT1) through the ubiquitin-proteasome pathway and restoring unsaturated fatty acid homeostasis. This study reveals the molecular mechanism of OL in RA intervention, identifies ACOT1 as a new potential target for RA treatment, and provides new insights into reprogramming fatty acid metabolism as a therapeutic strategy for RA.
In this study, researchers established a complete Freund’s adjuvant (CFA)-induced RA rat model and treated rats with 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. The results showed that OL significantly reduced joint swelling in RA rats, restored the normal structure of cartilage and synovium, and improved pathological changes in immune organs such as the thymus and spleen. OL also suppressed the abnormally high expression of CD3+ T cells and CD68+ macrophages in joint tissue, shifted macrophage polarization from pro-inflammatory M1 (CD86) to anti-inflammatory M2 (CD206) dominance, and inhibited the differentiation of CD4+ T cells into Th17 cells. Furthermore, OL dose-dependently reduced the serum levels of pro-inflammatory cytokines such as IL-1β, IL-6, IL-17, TNF-α, and RA diagnostic markers such as RF, CCP-Ab, CRP, and MMP-3 in RA rats.
Multi-omic profiling including metabolomics, MALDI mass spectrometry imaging, and proteomics demonstrated that OL corrects the dysregulation of unsaturated fatty acid (arachidonic acid, linoleic acid, α-linolenic acid, etc.) biosynthesis and metabolism in RA rats. in vitro Experiments confirmed that OL inhibits the proliferation of RA synovial fibroblasts (SFs), promotes their apoptosis, and suppresses the secretion of inflammatory cytokines. Mechanistically, cellular thermal shift assays, microscale thermophoresis, and surface plasmon resonance experiments show that ACOT1 has a dissociation constant (Kd) (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 enhanced the proteasomal degradation of ACOT1 via ubiquitination, thereby decreasing the expression of downstream stearoyl-CoA desaturase-1 (SCD1) and inhibiting the activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling. pathway and ultimately suppress SF inflammation and fibrosis. Furthermore, rescue experiments and inhibitor studies confirmed that OL exerts anti-inflammatory, anti-proliferative, and pro-apoptotic effects by targeting ACOT1 and regulating the arachidonic acid pathway and downstream JAK-STAT/PI3K-AKT signaling pathway.
RA is a chronic systemic autoimmune disease with a global prevalence of approximately 1%, and current treatments have limited efficacy and severe side effects. This study provides experimental evidence that OL is a potential therapeutic agent for rheumatoid arthritis, highlights the importance of targeting ACOT1 to modulate unsaturated fatty acid metabolism in rheumatoid arthritis treatment, and provides a new direction for the development of novel anti-rheumatoid drugs.
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Reference magazines:
Liu, H. others. (2026). Ovalactones alleviate rheumatoid arthritis by promoting ACOT1 degradation and restoring unsaturated fatty acid homeostasis through the ubiquitin-proteasome pathway. engineering. DOI: 10.1016/j.eng.2025.10.029. https://www.sciencedirect.com/science/article/pii/S2095809925006678?via%3Dihub
