Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Paederoside alleviates rheumatoid arthritis by targeting SMAD4 to suppress histone lactylation through inhibiting lactate transport in senescent macrophages.
СтатьяОбзорНазвание и аннотация: Перевод в очереди
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Chen Jiayao, Zhang Jing, Ma Yingjie, Chen Bocen, Jian Shaoqin, Chen Tong, Wang Wenguang, Xiao Man
Аннотация
BACKGROUND: 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.
PURPOSE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.
PURPOSE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.