Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovitis, hyperplasia of synovial cells, and progressive cartilage and bone degradation [1]. It impacts 0.5–1 % of the global population, predominantly women aged 40–60, with approximately 1.3 million cases in the United States and a prevalence of 0.4–0.7 % in India. The early phase of RA involves persistent synovial inflammation, intense inflammatory infiltration of granulocytes, macrophages, lymphocytes, and fibroblasts, leading to elevated levels of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukins, growth factors, proteolytic enzymes, and eicosanoids. Key signalling pathways, including nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK), further amplify inflammation [2]. Epidermal Growth Factor Receptor (EGFR), acting as an upstream regulator, becomes aberrantly activated and promotes synovial fibroblast proliferation and cytokine production. This activation triggers key downstream signalling pathways, including nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK), further amplifying the inflammatory response [3]. Our earlier research identified EGFR and Annexin A2 (AnxA2) as key drivers of inflammation that suppress the anti-inflammatory actions of Annexin A1 (AnxA1) in RA [4]. We initially established elevated expression of AnxA2 and HB-EGF in TNBC [5]. Subsequently, we demonstrated that AnxA2–galectin-3 (Gal-3) interactions further modulate EGFR signalling in HER2-negative breast cancer [6]. In RA, elevated EGFR expression correlates with disease severity by driving the production of pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β. AnxA2, also upregulated in RA, acts in synergy with EGFR to amplify inflammatory signalling and sustain chronic inflammation. We have also found that AnxA2 knockdown using siRNA or antibodies increased AnxA1 levels and membrane translocation, leading to reduced functional cytokines. Additionally, in vitro treatment with dexamethasone and AnxA2 antibodies improved AnxA1's interaction with EGFR in human synovial fibroblasts [4]. The relationship between EGFR-AnxA2 and AnxA1 is bidirectional; AnxA1 can influence EGFR signalling, while EGFR activation can downregulate AnxA1, creating a feedback loop that exacerbates inflammation [7].

Synthetic glucocorticoids, often used to manage inflammation, enhance anti-inflammatory proteins like AnxA1, highlighting their role in modulating inflammatory responses in RA [8,9]. Interestingly, pregnancy-induced remission in RA is linked to hormonal changes, particularly elevated progesterone and oestradiol, which shift the immune response toward an anti-inflammatory state [10]. AnxA1, an anti-inflammatory molecule, rises significantly during pregnancy, playing a key role in modulating inflammation [11]. Clinical studies show increased AnxA1 levels in maternal serum and amniotic fluid, especially in the second and third trimesters, suggesting its importance in RA remission [11,12]. Serum butyrate levels help stabilize AnxA1, potentially counteracting pro-inflammatory EGFR-AnxA2 signalling. This supports the hypothesis that mimicking pregnancy-induced remission through butyrate supplementation could offer a therapeutic approach for RA by enhancing AnxA1 levels and reducing inflammation [13].

Butyrate, a naturally occurring short-chain fatty acid from dietary fibre fermentation, offers a safer alternative to synthetic glucocorticoids. As a natural glucocorticoid, butyrate induces AnxA1, exerting anti-inflammatory effects [14,15]. Butyrate is also being explored as a therapeutic agent due to its role as a histone deacetylase (HDAC) inhibitor, promotes AnxA1 expression across multiple cell types. It enhances AnxA1 expression in various cancer models, including colon adenocarcinoma [16], melanoma [17] and prostate cancer [18]. Additionally, butyrate stimulates glucagon-like peptide-1 (GLP-1) secretion from intestinal L-cells, supporting metabolic health and helping prevent obesity and diabetes [19,20]. In gestational diabetes, placentas show reduced AnxA1 in the villous compartment, accompanied by increased DNA damage, apoptosis, and diminished expression of base excision repair (BER) pathway enzymes [12]. Given butyrate's natural origin and gut health benefits, butyrate presents a safer alternative to synthetic glucocorticoids, [16,17,21], particularly in pregnancy, where the synthetic glucocorticoids may pose risks to maternal and fetal health [22].

The current research underscores sodium butyrate's therapeutic potential in targeting EGFR-AnxA2 signalling in RA. In vitro studies revealed that sodium butyrate effectively downregulated EGFR and AnxA2 while increasing AnxA1 levels in RA synovial fibroblasts. In vivo findings from a collagen-induced arthritis (CIA) murine model indicated that sodium butyrate treatment led to reduced joint inflammation, better-preserved bone structure, and decreased disease severity. Radiological assessments revealed significant preservation of tibial and calcaneal integrity, alongside reduced bone erosion and joint space narrowing. Furthermore, in vivo analysis indicated lower expression of both EGFR and AnxA2, while reinforcing AnxA1 expression. Disrupting the EGFR-AnxA2 feedback loop, sodium butyrate emerges as a promising adjunctive therapy for RA, potentially mitigating radiological progression and improving patient outcomes.