Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects the joints, causing pain, swelling, and deformity [1]. The basic pathologic changes are the inflammatory proliferation of the synovium, migratory infiltration into the cartilage, and progressive articular cartilage and bone destruction, which may ultimately lead to joint deformity and loss of function [2], [3]. The inflammatory environment in the synovial area is regulated by a complex of cytokines and chemokines, such as tumor necrosis factor (TNF-α), Interferon-γ (INF-γ), interleukin 6 (IL-6), and interleukin 1β (IL-1β) [4], [5]. These inflammatory factors induce or exacerbate the inflammatory response by activating synoviocytes and attracting immune cells to congregate in the synovium [6]. Various studies have shown that several cytokines such as TNF-α, INF-γ, and IL-6 are involved in the pathogenesis of RA, resulting in damage to the joints and their tissues [7], [8], [9]. Therefore, inhibition of the expression of these cytokines can inhibit the progression of RA. Biological inhibitors against these cytokines and their receptors have been developed but are costly, necessitating the development of orally effective and cost-effective small molecule therapeutics [10], [11].

The JAK-STAT pathway is a key signaling pathway that is activated by cytokines such as TNF/INF and IL-6 [12]. These cytokines bind to cell surface receptors, which then activate intracellular structural domains. This activation leads to the recruitment of Janus Kinase (JAK), initiating the JAK pathway. The JAK pathway subsequently triggers the phosphorylation of the signal transducer and activator of the transcription (STAT) pathway [13]. Once activated, the STAT pathway is transferred to the nucleus of the cell, where it modulates the immune response. This activation can result in the high expression of inflammatory factors, including TNF-α, IL-1β, and IL-6, leading to an inflammatory storm [14]. The JAK family, consisting of JAK1, JAK2, JAK3, and TYK2, plays a crucial role in this process. These proteins bind to dimerized cytokine receptor chains, inducing inflammation, promoting cell proliferation, and regulating immune responses [15]. Among the STAT family members (STAT1, STAT2, STAT3, STAT4, STAT5, STAT6), STAT3 and STAT5 have been found to have pro-inflammatory and modulating roles in immune diseases [16], [17]. Numerous studies have demonstrated a close relationship between the activation of the JAK-STAT pathway in the onset and progression of RA [18], [19]. Therefore, blocking JAK or inhibiting the STAT pathway can inhibit the inflammatory response, slowing the progression of RA [20]. Inhibitors of the JAK pathway have been widely used in the clinical treatment of RA, such as filgotinib, tofacitinib, etc [21]. Thus, the JAK-STAT pathway plays a crucial role in the pathogenesis of RA.

Periplogenin is an active ingredient in the traditional Chinese medicine herb of cortex periplocae in China, belonging to the cardiac glycosides, with molecular formula C23H34O5. Periplogenin has demonstrated promising potential as a therapeutic agent for various diseases. Studies have shown that periplogenin can induce apoptosis of esophageal cancer cells by inhibiting the STAT3 pathway [22]. Additionally, periplogenin has been shown to improve the symptoms of psoriasis in a mouse model by inducing apoptosis of HACAT cells through anti-inflammation and regulating oxidative stress [23]. Furthermore, periplogenin may have the ability to ameliorate immune disorders by inhibiting inflammatory responses [24]. These findings suggest that periplogenin could be a valuable candidate for developing novel treatments for cancer, psoriasis, and other immune disorders. We screened potential pathways of RA and periplogenin, including the Ras, PI3K-AKT, and JAK-STAT pathways, and the JAK-STAT pathway plays a crucial role in RA [25], [26]. The molecular targets of periplogenin and the mechanism of ameliorating RA pathology remain unclear, therefore, in this study, the mechanism of periplogenins' action was verified in vivo and in vitro.