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<p>Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by dysregulated immune responses, persistent synovial inflammation, and progressive joint destruction. Shikonin (SKN), a bioactive naphthoquinone derived from <i>Lithospermum erythrorhizon</i> and related Boraginaceae species, has demonstrated broad immunomodulatory and anti-inflammatory activities in experimental studies. This systematic review and meta-analysis aimed to critically evaluate the immunopharmacological efficacy and underlying mechanisms of SKN in preclinical in vivo models of RA. A comprehensive literature search was conducted in PubMed, ScienceDirect, and Google Scholar to identify eligible studies published up to November 2025. In vivo studies investigating the effects of SKN in experimental RA models were included. Data extraction was performed using a predefined protocol, and risk of bias was assessed using the SYRCLE tool. Quantitative synthesis was conducted using Review Manager (RevMan) version 5.4, with standardized mean differences (SMDs) and 95% confidence intervals (CIs) calculated for continuous outcomes. Twelve studies met the inclusion criteria, employing collagen-induced, adjuvant-induced, or complete Freund adjuvant arthritis models in mice and rats. SKN was predominantly administered via oral gavage at doses ranging from 1.0 to 5.2&#xa0;mg/kg. Meta-analysis revealed that SKN significantly reduced paw edema and arthritis scores and improved joint histopathology. Immunopharmacological effects included suppression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), enhancement of anti-inflammatory IL-10, and upregulation of FoxP3⁺ regulatory T cells. Mechanistic studies implicated modulation of key immune signaling pathways, including AMPK/mTOR, PI3K/AKT, MAPK, NF-κB, and JAK/STAT. SKN exhibits potent immunomodulatory and anti-arthritic effects in preclinical RA models by targeting multiple cytokine-driven and immune signaling pathways. These findings support its potential as an immunopharmacological agent for autoimmune inflammatory diseases, warranting further translational and safety-focused investigations.</p>

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Immunopharmacological effects of shikonin in experimental rheumatoid arthritis: a systematic review and meta-analysis of in vivo studies

  • 期刊论文

  • 发表日期：

    2026年3月30日

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  • Muhammad Muzammil Nazir,
  • Saima Muzammil,
  • Muhammad Mujammil Nazir,
  • Sara Nazir,
  • Asma Ashraf

摘要

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by dysregulated immune responses, persistent synovial inflammation, and progressive joint destruction. Shikonin (SKN), a bioactive naphthoquinone derived from Lithospermum erythrorhizon and related Boraginaceae species, has demonstrated broad immunomodulatory and anti-inflammatory activities in experimental studies. This systematic review and meta-analysis aimed to critically evaluate the immunopharmacological efficacy and underlying mechanisms of SKN in preclinical in vivo models of RA. A comprehensive literature search was conducted in PubMed, ScienceDirect, and Google Scholar to identify eligible studies published up to November 2025. In vivo studies investigating the effects of SKN in experimental RA models were included. Data extraction was performed using a predefined protocol, and risk of bias was assessed using the SYRCLE tool. Quantitative synthesis was conducted using Review Manager (RevMan) version 5.4, with standardized mean differences (SMDs) and 95% confidence intervals (CIs) calculated for continuous outcomes. Twelve studies met the inclusion criteria, employing collagen-induced, adjuvant-induced, or complete Freund adjuvant arthritis models in mice and rats. SKN was predominantly administered via oral gavage at doses ranging from 1.0 to 5.2 mg/kg. Meta-analysis revealed that SKN significantly reduced paw edema and arthritis scores and improved joint histopathology. Immunopharmacological effects included suppression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), enhancement of anti-inflammatory IL-10, and upregulation of FoxP3⁺ regulatory T cells. Mechanistic studies implicated modulation of key immune signaling pathways, including AMPK/mTOR, PI3K/AKT, MAPK, NF-κB, and JAK/STAT. SKN exhibits potent immunomodulatory and anti-arthritic effects in preclinical RA models by targeting multiple cytokine-driven and immune signaling pathways. These findings support its potential as an immunopharmacological agent for autoimmune inflammatory diseases, warranting further translational and safety-focused investigations.