Salicylalazine: A novel therapeutic agent targeting TLR4/NLRP3/GSDMD-mediated pyroptosis in rheumatoid arthritis

•SAZ reduced paw volume significantly in FA and CFA arthritis models, most notably on day 10 (FA) and day 28 (CFA) (p < 0.001).•SAZ improved body weight, mobility, flexion pain, and stance scores over 28 days.•SAZ increased GSH, CAT, SOD levels and decreased MDA, reducing oxidative stress.•SAZ modulated TLR4/NLRP3/GSDMD-mediated pyroptosis by lowering inflammatory mediator expression.•Inflammatory markers (CRP, RF, anti-CCP) restored to near-normal levels with SAZ treatment. Joint pain and functional impairment are hallmarks of arthritis, a painful inflammatory disease. Salicylalazine (SAZ), an anti-inflammatory compound, has demonstrated promise in modulating inflammation, thereby being selected in the current study to unveil its anti-arthritic potential. The aim behind this study was to assess the anti-arthritic properties of salicylalazine via evaluating its impact on paw volume, arthritic scores, oxidative stress indicators, and significant inflammatory mediators. The arthritic potential of SAZ was estimated first through the formaldehyde (FA) model to screen the most effective dose of SAZ, followed by the Complete Freund’s adjuvant (CFA) model. Over a 28-day period, we monitored parameters such as paw edema, arthritic index, body weight, flexion pain, mobility, and stance score. Oxidative stress markers (GSH, CAT, SOD, MDA), serological markers (CRP, RF, anti-CCP), and gene expression of key inflammatory mediators (TLR4, MyD88, NFκB, NLRP3, ASC, IL-1β, IL-18, caspase-1, GSDMD) were assessed. SAZ treatment led to a substantial decrease in paw volume in both arthritis models, with the most pronounced effects observed on day 10 for the formaldehyde model and day 28 for the CFA model (p