Evaluating the preclinical efficacy of naringenin in rheumatoid arthritis: a meta-analysis of in vivo studies

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation, joint destruction, and systemic complications. Despite the availability of conventional therapies, limitations such as adverse effects and incomplete remission necessitate alternative treatment options. Naringenin, a flavanone found abundantly in citrus fruits, exhibits anti-inflammatory, immunomodulatory, and antioxidant properties, making it a potential therapeutic agent for RA. This systematic review and meta-analysis aimed to evaluate the efficacy of naringenin in preclinical in vivo models of RA by synthesizing available evidence on its therapeutic effects on clinical, biochemical, and histopathological parameters. A comprehensive literature search was conducted in PubChem, Google Scholar, and Science Direct following PRISMA 2020 guidelines. Twelve eligible in vivo studies were identified using established inclusion criteria. Data were extracted for arthritis scores, paw volume, body weight, inflammatory cytokines, oxidative stress markers, histopathological outcomes, and cartilage degradation enzymes. Statistical analyses were performed using RevMan 5.4, and effect sizes were calculated as standardized mean differences (SMD) with 95% confidence intervals (CI) under a random-effects model. Naringenin significantly reduced arthritis severity (SMD = - 3.50), paw volume (SMD = - 1.78), and levels of TNF-α (SMD = - 4.94), IL-6 (SMD = - 2.97), IL-1β (SMD = - 5.55), and IL-17 (SMD = - 1.22), while improving antioxidant defenses (SOD, GSH) and reducing oxidative stress (MDA). It also improved histopathology and body weight, and decreased cartilage-degrading enzymes (MMP-3, MMP-9). Heterogeneity was generally low to moderate across analyses. Subgroup analyses revealed that therapeutic outcomes varied by arthritis model, dosage, and treatment duration. Naringenin demonstrates strong anti-arthritic effects in animal models through modulation of inflammatory cytokines, oxidative stress markers, and joint pathology. These findings support its potential as a candidate for further investigation in clinical settings. However, translational studies and human trials are essential to validate its safety, efficacy, and pharmacokinetics in RA management.

Keywords: Cytokines; Flavonoid; In vivo; Inflammation; MMPs; Meta-analysis; NF-κB; Naringenin; Oxidative stress; Rheumatoid arthritis.