Natural compound obakulactone shows therapeutic potential for rheumatoid arthritis

A new study published in Engineering reveals that obakulactone (OL), a natural tetracyclic triterpenoid isolated from Phellodendri cortex, exerts a therapeutic effect on rheumatoid arthritis (RA) by promoting the degradation of acyl coenzyme A thioesterase 1 (ACOT1) via the ubiquitin‒proteasome pathway and restoring the homeostasis of unsaturated fatty acids. The research clarifies the molecular mechanism of OL in RA intervention and identifies ACOT1 as a novel potential target for RA treatment, providing new insights into fatty acid metabolism reprogramming as a therapeutic strategy for RA.

In the study, researchers established a complete Freund's adjuvant (CFA)-induced RA rat model 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. The results showed that OL significantly alleviated joint swelling in RA rats, restored the normal structure of cartilage and synovium, and improved the pathological changes of immune organs including thymus and spleen. OL also suppressed the abnormally high expression of CD3⁺ T cells and CD68⁺ macrophages in joint tissues, shifted macrophage polarization from proinflammatory M1 (CD86) to anti-inflammatory M2 (CD206) dominant, and inhibited the differentiation of CD4⁺ T cells into Th17 cells. In addition, OL dose-dependently reduced the serum levels of proinflammatory cytokines such as IL-1β, IL-6, IL-17, and TNF-α, as well as RA diagnostic markers including RF, CCP-Ab, CRP, and MMP-3 in RA rats.

Multiomics profiling, including metabolomics, MALDI mass spectrometry imaging, and proteomics, demonstrated that OL corrected the dysregulated biosynthesis and metabolism of unsaturated fatty acids (e.g., arachidonic acid, linoleic acid, and α-linolenic acid) in RA rats. In vitro experiments confirmed that OL inhibited the proliferation of RA synovial fibroblasts (SFs), promoted their apoptosis, and suppressed the secretion of inflammatory cytokines. Mechanistically, cellular thermal shift assays, microscale thermophoresis, and surface plasmon resonance experiments verified that ACOT1 is the direct target of OL, with a dissociation constant (K_d) 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 enhanced the ubiquitination-mediated proteasomal degradation of ACOT1, thereby reducing the expression of downstream stearoyl-CoA desaturase-1 (SCD1), inhibiting the activation of Janus kinase (JAK)–signal transducer and activator of transcription (STAT) and phosphoinositide 3-kinase (PI3K)–protein kinase B (AKT) signaling pathways, and ultimately suppressing inflammation and fibrosis in SFs. Further rescue experiments and inhibitor studies confirmed that OL exerts its anti-inflammatory, antiproliferative, and proapoptotic effects by targeting ACOT1 to regulate the arachidonic acid pathway and the downstream JAK–STAT/PI3K–AKT signaling pathways.

RA is a chronic systemic autoimmune disease with a global prevalence of approximately 1%, and current treatments have limited efficacy and severe adverse effects. This study provides experimental evidence for OL as a potential therapeutic agent for RA and highlights the significance of targeting ACOT1 and regulating unsaturated fatty acid metabolism in RA treatment, offering a new direction for the development of novel anti-RA drugs.