芍药苷通过靶向SMAD4抑制衰老巨噬细胞中的乳酸转运来抑制组蛋白乳酸化，从而缓解类风湿性关节炎
Paederoside alleviates rheumatoid arthritis by targeting SMAD4 to suppress histone lactylation through inhibiting lactate transport in senescent macrophages.
摘要(中文译文)
类风湿关节炎（RA）是一种以持续性滑膜炎症和进行性关节破坏为特征的慢性自身免疫性疾病。衰老巨噬细胞通过代谢重编程成为RA发病机制的关键驱动因素，导致细胞内乳酸蓄积和组蛋白乳酸化，进而促进促炎细胞因子的表达和滑膜增生。鸡矢藤苷（Paederoside）是一种来源于鸡矢藤（Paederia scandens）的环烯醚萜苷，已显示出抗炎作用，但其在RA中的精确分子靶点仍不清楚。本研究旨在阐明鸡矢藤苷通过靶向SMAD4-MCT1轴抑制衰老巨噬细胞中乳酸转运和组蛋白乳酸化从而缓解RA的机制。采用博来霉素（BLM）建立衰老RAW264.7巨噬细胞模型。使用ELISA、qRT-PCR、Western blot和免疫荧光评估鸡矢藤苷对巨噬细胞极化、乳酸代谢和组蛋白乳酸化的影响。采用分子对接、细胞热位移分析（CETSA）和双荧光素酶报告基因实验验证鸡矢藤苷与SMAD4之间的相互作用。使用胶原诱导性关节炎（CIA）小鼠模型评估鸡矢藤苷的体内治疗效果。鸡矢藤苷通过抑制单羧酸转运蛋白1（MCT1）表达，显著降低BLM诱导的衰老巨噬细胞中乳酸蓄积和H3K14乳酸化（H3K14la）水平。机制上，鸡矢藤苷直接结合SMAD4的Arg100位点，阻断其核转位及对Mct1的转录激活。这导致乳酸流入减少，促炎基因（包括趋化因子Ccl7、Cxcl1和基质金属蛋白酶Mmp1）启动子区域的H3K14la水平降低，并促使巨噬细胞从促炎M1型向抗炎M2型极化转变。因此，鸡矢藤苷抑制了滑膜成纤维细胞的增殖和侵袭。在CIA模型中，鸡矢藤苷减轻关节肿胀、骨侵蚀和滑膜炎症的效果与甲氨蝶呤相当。鸡矢藤苷通过靶向SMAD4抑制MCT1介导的乳酸转运，从而抑制组蛋白乳酸化和促炎巨噬细胞极化，进而缓解RA。这些发现凸显了SMAD4-MCT1轴作为RA治疗中一个有前景的代谢-表观遗传靶点，并支持鸡矢藤苷作为老年RA患者精准治疗先导化合物的潜力。
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by persistent synovial inflammation and progressive joint destruction. Senescent macrophages are key drivers of RA pathogenesis through metabolic reprogramming, leading to intracellular lactate accumulation and histone lactylation, which promotes the expression of pro-inflammatory cytokines and synovial hyperplasia. Paederoside, an iridoid glycoside from Paederia scandens, has demonstrated anti-inflammatory effects, but its precise molecular targets in RA remain unclear. This study aimed to elucidate the mechanism by which paederoside alleviates RA by targeting the SMAD4-MCT1 axis to suppress lactate transport and histone lactylation in senescent macrophages. A senescent RAW264.7 macrophage model was established using bleomycin (BLM). The effects of paederoside on macrophage polarisation, lactate metabolism, and histone lactylation were assessed using ELISA, qRT-PCR, Western blot, and immunofluorescence. Molecular docking, cellular thermal shift assay (CETSA), and dual-luciferase reporter assays were employed to validate the interaction between paederoside and SMAD4. A collagen-induced arthritis (CIA) mouse model was used to evaluate the therapeutic efficacy of paederoside in vivo. Paederoside significantly reduced BLM-induced lactate accumulation and H3K14 lactylation (H3K14la) in senescent macrophages by inhibiting monocarboxylate transporter 1 (MCT1) expression. Mechanistically, paederoside directly binds to SMAD4 at Arg100, blocking its nuclear translocation and transcriptional activation of Mct1. This led to decreased lactate influx, reduced H3K14la levels at the promoters of pro-inflammatory genes, including chemokines (Ccl7, Cxcl1) and matrix metalloproteinase Mmp1, and a shift from pro-inflammatory M1 to anti-inflammatory M2 macrophage polarisation. Consequently, paederoside suppressed the proliferation and invasion of synovial fibroblasts. In the CIA model, paederoside attenuated joint swelling, bone erosion, and synovial inflammation comparably to methotrexate. Paederoside alleviates RA by targeting SMAD4 to inhibit MCT1-mediated lactate transport, thereby suppressing histone lactylation and pro-inflammatory macrophage polarisation. These findings highlight the SMAD4-MCT1 axis as a promising metabolic-epigenetic target for RA therapy and support paederoside as a lead compound for the precision treatment of elderly RA patients.
如何引用
AMA
Jiayao Chen, Jing Zhang, Yingjie Ma, Bocen Chen, Shaoqin Jian, Tong Chen, et al. Paederoside alleviates rheumatoid arthritis by targeting SMAD4 to suppress histone lactylation through inhibiting lactate transport in senescent macrophages.. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2026; doi:10.1016/j.phymed.2026.158523.
APA
Jiayao Chen, Jing Zhang, Yingjie Ma, Bocen Chen, Shaoqin Jian, Tong Chen, et al (2026). Paederoside alleviates rheumatoid arthritis by targeting SMAD4 to suppress histone lactylation through inhibiting lactate transport in senescent macrophages.. Phytomedicine : international journal of phytotherapy and phytopharmacology. https://doi.org/10.1016/j.phymed.2026.158523
GB/T 7714
Jiayao Chen, Jing Zhang, Yingjie Ma, Bocen Chen, Shaoqin Jian, Tong Chen, et al. Paederoside alleviates rheumatoid arthritis by targeting SMAD4 to suppress histone lactylation through inhibiting lactate transport in senescent macrophages.[J]. Phytomedicine : international journal of phytotherapy and phytopharmacology, 2026 doi:10.1016/j.phymed.2026.158523.
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