Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Sidaxue ameliorates rheumatoid arthritis by inhibiting synovial neutrophil migration: Insights from an integrated multi-omics analysis.
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Xu Bingyang, Liu Shuhan, Chen Mingxie, Li Xinyue, Bi Xuan, Xue Xiangqian, Cheng Peijun, Guo Xiaona, Liu Leilei, Yang Yingting, Sun Jianfei, Wu Ning
Аннотация
BACKGROUND: The therapeutic outcomes for rheumatoid arthritis (RA) remain unsatisfactory. Neutrophil migration and activation in the synovium are pivotal drivers of RA pathology. Sidaxue (SX), a traditional Miao herbal formula, has shown anti-RA potential, yet its mechanism concerning neutrophil migration is unclear.
PURPOSE: This study aims to evaluate the effects of SX on neutrophil migration in RA and to uncover the novel molecular mechanisms.
METHODS: We integrated bulk RNA sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) with Mendelian randomization (MR) to pinpoint critical targets. Ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) characterized SX's components, with binding affinities evaluated by molecular docking and dynamics simulations. Functional assays used SX-containing serumin vitro and a collagen-induced arthritis (CIA) model in vivo.
RESULTS: Multi-omics analysis identified the RAC1/PAK1 pathway as central to neutrophil migration in RA. MR analysis nominated PAK1 as a potential drug target. We identified 38 major compounds in SX, which demonstrated high binding affinity to RAC1 and PAK1. SX-containing serum potently inhibited phorbol 12-myristate 13-acetate (PMA)-induced neutrophil migration, neutrophil extracellular traps (NETs) formation, and pro-inflammatory cytokine release. These effects were mediated through suppression of the RAC1/PAK1/LIMK1/Cofilin1 signaling axis, a finding corroborated by rescue experiments with the modulator Fingolimod hydrochloride (FTY). In vivo, SX alleviated joint swelling and synovitis in CIA rats, concurrently downregulating this pathway.
CONCLUSION: SX ameliorates RA by inhibiting neutrophil migration and activation via the RAC1/PAK1/LIMK1/Cofilin1 pathway. This work unveils the immune-regulatory mechanism of SX, supporting its development as a natural therapeutic for RA.
PURPOSE: This study aims to evaluate the effects of SX on neutrophil migration in RA and to uncover the novel molecular mechanisms.
METHODS: We integrated bulk RNA sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) with Mendelian randomization (MR) to pinpoint critical targets. Ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) characterized SX's components, with binding affinities evaluated by molecular docking and dynamics simulations. Functional assays used SX-containing serumin vitro and a collagen-induced arthritis (CIA) model in vivo.
RESULTS: Multi-omics analysis identified the RAC1/PAK1 pathway as central to neutrophil migration in RA. MR analysis nominated PAK1 as a potential drug target. We identified 38 major compounds in SX, which demonstrated high binding affinity to RAC1 and PAK1. SX-containing serum potently inhibited phorbol 12-myristate 13-acetate (PMA)-induced neutrophil migration, neutrophil extracellular traps (NETs) formation, and pro-inflammatory cytokine release. These effects were mediated through suppression of the RAC1/PAK1/LIMK1/Cofilin1 signaling axis, a finding corroborated by rescue experiments with the modulator Fingolimod hydrochloride (FTY). In vivo, SX alleviated joint swelling and synovitis in CIA rats, concurrently downregulating this pathway.
CONCLUSION: SX ameliorates RA by inhibiting neutrophil migration and activation via the RAC1/PAK1/LIMK1/Cofilin1 pathway. This work unveils the immune-regulatory mechanism of SX, supporting its development as a natural therapeutic for RA.