类风湿性关节炎 (RA) 是一种持久的自身免疫炎症性疾病，其特征是持续的关节炎症、滑膜增生、骨质侵蚀和软骨退化。表现出“肿瘤样”特征的成纤维细胞样滑膜细胞 (FLS) 是该机制的核心ADP-核糖基化因子样 4c (ARL4C) 作为 Ras 样小 GTP 结合蛋白发挥作用，显着影响肿瘤迁移、侵袭和增殖。然而，ARL4C 是否参与刺激表现出“肿瘤”的 RA FLS 仍不确定-like”特征，从而促进 RA 的进步。在我们的研究中，我们首次通过对单细胞 RNA 测序 (scRNA-seq) 和批量 RNA 测序 (Bulk-seq) 数据集的综合审查，发现激活的成纤维细胞样滑膜细胞 (FLS) 表现出高表达ARL4C 的存在，并且来自 RA 患者的 FLS 中的 ARL4C 蛋白表达显着超过骨关节炎 (OA) 和创伤性损伤 (trauma) 个体中观察到的表达。 ARL4C 基因的沉默通过阻碍细胞的转变而显着阻碍 RA FLS 的增殖细胞从G0/G1期进入S期，细胞凋亡加剧，迁移和侵袭能力减弱。 ARL4C基因沉默的RA FLS与单核细胞/巨噬细胞的共培养显着抑制了单核细胞/巨噬细胞向M1的极化以及M2向M1的复极化。此外，关节内注射shARL4C显着减轻了胶原蛋白中的滑膜炎症和软骨侵蚀。诱导性关节炎（CIA）大鼠。总之，我们的发现表明，ARL4C 通过触发 RA FLS 内的 PI3K/AKT 和 MAPK 信号通路，在与 RA 相关的滑膜炎症、软骨退化和骨侵蚀中发挥核心作用。ARL4C 有望成为开发的前瞻性靶点针对 FLS 的药剂，旨在解决 RA。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Rheumatoid arthritis (RA) is an enduring autoimmune inflammatory condition distinguished by continual joint inflammation, hyperplasia of the synovium, erosion of bone, and deterioration of cartilage.Fibroblast-like synoviocytes (FLSs) exhibiting "tumor-like" traits are central to this mechanism.ADP-ribosylation factor-like 4c (ARL4C) functions as a Ras-like small GTP-binding protein, significantly impacting tumor migration, invasion, and proliferation.However, it remains uncertain if ARL4C participates in the stimulation of RA FLSs exhibiting "tumor-like" features, thereby fostering the advancement of RA. In our investigation, we unveiled, for the inaugural instance, via the amalgamated scrutiny of single-cell RNA sequencing (scRNA-seq) and Bulk RNA sequencing (Bulk-seq) datasets, that activated fibroblast-like synoviocytes (FLSs) showcase high expression of ARL4C, and the ARL4C protein expression in FLSs derived from RA patients significantly surpasses that observed in individuals with osteoarthritis (OA) and traumatic injury (trauma).Silencing of the ARL4C gene markedly impeded the proliferation of RA FLSs by hindered the transition of cells from the G0/G1 phase to the S phase, and intensified cell apoptosis and diminished the migratory and invasive capabilities. Co-culture of ARL4C gene-silenced RA FLSs with monocytes/macrophages significantly inhibited the polarization of monocytes/macrophages toward M1 and the repolarization of M2 to M1.Furthermore, intra-articular injection of shARL4C significantly alleviated synovial inflammation and cartilage erosion in collagen-induced arthritis (CIA) rats. In conclusion, our discoveries propose that ARL4C assumes a central role in the synovial inflammation, cartilage degradation, and bone erosion associated with RA by triggering the PI3K/AKT and MAPK signaling pathways within RA FLSs.ARL4C holds promise as a prospective target for the development of pharmaceutical agents targeting FLSs, with the aim of addressing RA.Copyright © 2024 Elsevier B.V. All rights reserved.