Oxyimperatorin Suppresses the Pathologies of Rheumatoid Arthritis and the Growth of Synovial Organoids Through Targeting the <scp>PI3K</scp> / <scp>AKT</scp> Pathway

Oxyimperatorin (OIMP) is a coumarin extracted from the roots of the traditional Chinese medicinal plant Bai Zhi (Angelica dahurica). This study aimed to investigate the potential effects and underlying mechanisms of OIMP in the progression of rheumatoid arthritis (RA). CCK-8, immunofluorescence, flow cytometry, and EdU assays were performed to evaluate the effects of OIMP on the functions of RA fibroblast-like synoviocytes (RA-FLSs). RNA sequencing (RNA-seq), quantitative real-time PCR (RT-qPCR), Western blot, kinase assay, and network pharmacological analysis were conducted to elucidate the mechanism of action of OIMP in RA. OIMP inhibited the proliferation of RA-FLSs by suppressing DNA replication and inducing cell cycle arrest. It also promoted the apoptosis and impaired the migratory and invasive capabilities of RA-FLSs. Moreover, OIMP disrupted the cell cycle by downregulating the mRNA and protein levels of cyclin B1 and cyclin-dependent kinase 1 (CDK1), and promoted apoptosis by reducing survivin expression and inducing DNA damage. In vivo, OIMP suppressed synovial organoid growth and alleviated symptoms in collagen-induced arthritis (CIA) mice. RNA-seq and Western blot further confirmed that OIMP inhibited the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling axis. Network pharmacological analysis suggested a pivotal role of the PI3K/AKT pathway in mediating OIMP's effects in RA. Additionally, OIMP was shown to bind to AKT1. In conclusion, OIMP may act as a potential AKT1 inhibitor that suppresses the pathologies of RA through targeting the PI3K/AKT pathway.