Multiple sclerosis (MS) is a demyelinating autoimmune disease characterized by early onset, for which the interaction of genetic and environmental factors is crucial. Dysregulation of the immune system as well as myelinization-de-myelinization has been shown to correlate with changes in RNA, including non-coding RNAs. Recently, circular RNAs (circRNAs) have emerged as a key player in the complex network of gene dysregulation associated with MS. Despite several efforts, the mechanisms driving circRNA regulation and dysregulation in MS still need to be properly elucidated. Here, we explore the panorama of circRNA expression in PBMCs purified from five newly diagnosed MS patients and five healthy controls (HCs) using the Arraystar Human circRNAs microarray. Experimental validation was then carried out in a validation cohort, and a possible correlation with disease severity was tested. We identified 64 differentially expressed circRNAs, 53 of which were downregulated in PBMCs purified from MS compared to the HCs. The discovery dataset was subsequently validated using qRT-PCR with an independent cohort of 20 RRMS patients and 20 HCs. We validated seven circRNAs differentially expressed in the RRMS group versus the HC group. hsa_circ_0000518, hsa_circ_0000517, hsa_circ_0000514, and hsa_circ_0000511 were significantly upregulated in the MS group, while hsa_circ_0018905, hsa_circ_0048764, and hsa_circ_0003445 were significantly downregulated; Among them, the expression level of hsa_circ_0018905 was significantly decreased in patients showing a higher level of disability and in progressive forms of MS. We described the circRNAs expression profile of PBMCs in newly diagnosed MS patients and proposed hsa_circ_0018905 as potential MS biomarker.

B-cell activating factor (BAFF) is a cytokine that plays a critical role in the proliferation and differentiation of B cells. We have previously demonstrated that its inherited overexpression is associated with increased circulating B cell and immunoglobulin levels, correlating with increased risk of multiple sclerosis and systemic lupus erythematosus. These findings suggest that enhanced BAFF expression may be involved in the causal biology of these disorders, thus supporting the rationale for therapeutic inhibition of this cytokine. However, to date, no small-molecule modulator capable of inhibiting BAFF is available. We therefore employed a virtual screening approach to analyze a library of 275,561 small molecules, followed by in vitro validation of 218 selected compounds with potential to disrupt the interaction between BAFF and its receptor BAFFR. Our results identified two promising small molecules, C45 and C145, belonging to the substituted 2-pyrrolinone family, which effectively inhibited BAFF activity. These compounds warrant further investigation as potential therapeutic agents for BAFF-driven autoimmune diseases.