Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterised by persistent synovial inflammation, joint destruction, and progressive disability. It arises from a multifaceted interplay of genetic, environmental, and immunological factors, ultimately resulting in excessive production of pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) (Ding et al., 2023, Gao et al., 2024, Guo et al., 2018). These mediators are central to immune dysregulation in RA and contribute to both local joint pathology and systemic inflammation (Hirano, 2021, Wei et al., 2015). Despite advances in treatment, including disease-modifying anti-rheumatic drugs (DMARDs) and biologics, many patients experience inadequate responses or adverse effects. This underscores the need for safe adjunctive therapies that act through alternative or complementary mechanisms (Jung et al., 2023, Zhao et al., 2022).

In the context of RA, several transcription factors— Retinoic Acid Receptor-Related Orphan Receptor Gamma t (RORγt), Nuclear Factor-kappa B (NF-κB), T-box Expressed in T Cells (T-bet), Forkhead Box P3 (FoxP3), GATA Binding Protein 3 (GATA3), and Peroxisome Proliferator-Activated Receptor Gamma (PPARγ)—play critical roles in T-helper cell differentiation (T-helper 1 (Th1), T-helper 2 (Th2), T-helper 17 (Th17)), immune tolerance (Regulatory T Cells (Treg)), immune tolerance (Treg), and regulation of inflammatory cytokines (Afzali et al., 2007, Jiang et al., 2021, Ungethuem et al., 2010). RORγt and NF-κB, in particular, are associated with the production of Interleukin-17 (IL-17), TNF-α, and IL-1β—key mediators implicated in synovial inflammation as well as in peripheral and central sensitisation, processes that underlie heightened pain perception and hyperalgesia (Kamel et al., 2022, Pouw et al., 2022, Sikorska et al., 2019, Tsuchiya et al., 2010). NF-κB–driven upregulation of TNF-α and IL-1β sensitises peripheral nociceptors and amplifies local inflammatory signalling, while Th17-derived IL-17 promotes neutrophil recruitment and nociceptive pathway activation; together these mechanisms facilitate microglial activation and central sensitisation in the spinal cord, ultimately sustaining chronic pain in RA (Cascão et al., 2010, Nejatbakhsh Samimi et al., 2020, Vergne-Salle and Bertin, 2021).

RORγt and NF-κB, in particular, are associated with the production of IL-17 and other mediators involved in synovial inflammation and pain, while FoxP3 is essential for regulatory T cell function and immune suppression (He and Feng, 2025, Nejatbakhsh Samimi et al., 2020, Roeleveld and Koenders, 2015). Prior research has shown that these genes are modifiable by pharmacologic agents and lifestyle interventions in autoimmune diseases (Kiełbowski et al., 2024, Marinho et al., 2017, Morvaridi et al., 2025, Nasl-Khameneh et al., 2023, Radu et al., 2025). However, the specific impact of saffron supplementation on these gene expression profiles in RA patients remains poorly understood.

Saffron (Crocus sativus L.) is a medicinal herb with active components such as crocin, crocetin, and safranal, which have shown anti-inflammatory, antioxidant, and immunomodulatory effects. Studies suggest that saffron may alleviate symptoms like pain and fatigue in chronic inflammatory disorders and modulate immune responses at the gene expression level (Kciuk et al., 2024, Zeinali et al., 2019). These effects are thought to occur through the suppression of key inflammatory pathways such as NF-κB, regulation of cytokine production, and enhancement of antioxidant defense systems (Anaeigoudari et al., 2023, Mashmoul et al., 2013). Furthermore, saffron appears to influence immune cell differentiation, particularly by shifting the Th1/Th17 balance toward a regulatory phenotype, enhancing Treg responses, and mitigating oxidative stress through increased antioxidant enzyme activity. These interrelated mechanisms could help reduce chronic inflammation and promote immune homoeostasis in RA (Baradaran Rahimi et al., 2023, Bastani et al., 2022, Boskabady et al., 2011, Hatziagapiou et al., 2019, Khazdair et al., 2021, Kondo et al., 2023, Rashid et al., 2024, Zeinali et al., 2019).

Although saffron’s anti-inflammatory effects have been documented in several chronic conditions, there is limited evidence regarding its effect on immune gene expression in RA. Exploring this aspect may reveal novel mechanisms of action and support its use as a complementary therapy (Maqbool et al., 2022, Rashid et al., 2024). Furthermore, robust clinical studies are needed to evaluate its therapeutic value beyond symptom relief, particularly regarding molecular immune modulation (Anaeigoudari et al., 2023, Kciuk et al., 2024, Zeinali et al., 2019).

This study aims to assess the effects of saffron supplementation not only on inflammatory biomarkers and disease activity but also on immune-related gene expression in individuals with active RA. By integrating clinical outcomes with molecular analyses, we seek to clarify saffron’s role as a complementary therapeutic strategy that addresses both symptom relief and immune modulation.