High mobility group box 1 may serve as a new therapeutic target for rheumatoid arthritis

Inadequate management of rheumatoid arthritis (RA) can lead to joint deformity, loss of function, and a decline in the patient’s social engagement and quality of life. This, in turn, can impose a substantial economic burden on both the patient’s family and society. Therefore, it is crucial to develop new biomarkers and comprehensive approaches that can accurately evaluate the patient’s condition. A recent study published in the European Journal of Medical Research reported a significant elevation of high mobility group box 1 (HMGB1) levels in patients with RA, indicating its potential to serve as a novel therapeutic target. 

The prospective cohort study conducted by Dr. Zhang and colleagues involved 124 patients with RA who were treated with metformin along with conventional therapy (methotrexate, hydroxychloroquine sulfate, and sulfasalazine) and 98 RA patients  who had undergone only conventional therapy. In patients with a disease activity score (DAS)-28 score of ≥2.6, the levels of HMGB1, C-reactive protein (CRP), interleukin (IL)-6, CD4+ expression, and CD4+/CD8+ ratio were significantly increased. During the study period, the serum HMGB1 and cytokine levels of the metformin group decreased more quickly. Pearson’s analysis showed that HMGB1 had a positive correlation with IL-6, tumor necrosis factor α (TNF-α), CRP, CD4+, CD4+/CD8+ ratio, and visual analogue score (VAS) scores. HMGB1 could be a potential diagnostic biomarker for RA patients in the active phase, and serum HMGB1 (95% CI 1.133-1.397, P <0.001) was associated with active RA. 

HMGB1 is a highly conserved nucleoprotein found in all cell types. Recent studies have unveiled its pivotal roles in regulating inflammation and responses to cells and tissues. Additionally, HMGB1 mediates inflammatory responses in various diseases and physiological processes by promoting the formation of inflammatory corpuscles, which activate inflammation-mediated cell death pathways. Previous research has indicated that HMGB1 can activate inflammatory pathways in RA, and inhibiting HMGB1 can suppress inflammatory responses in animal models of RA. 

The present study findings suggest that serum HMGB1 is linked to active RA, indicating its potential as both a therapeutic target and a diagnostic biomarker for patients with active RA. Exploring new therapeutic targets can aid in the management of RA and contribute to improving the overall well-being of patients. A deeper understanding of these molecular pathways can pave the way for more precise and personalized treatments. 


  1. Zhang L, Zhou Y, Jiang S, Fan Y, Huang J, Xiao B, et al. Effects of metformin therapy on HMGB1 levels in rheumatoid arthritis patients. European Journal of Medical Research. 2023 Nov 15;28(1):512.  
  1. Cecchinato V, D’Agostino G, Raeli L, Nerviani A, Schiraldi M, Danelon G, et al. Redox-Mediated Mechanisms Fuel Monocyte Responses to CXCL12/HMGB1 in Active Rheumatoid Arthritis. Front Immunol. 2018;9:2118.  
  1. Lu X, Gong S, Wang X, Hu N, Pu D, Zhang J, et al. Celastrol Exerts Cardioprotective Effect in Rheumatoid Arthritis by Inhibiting TLR2/HMGB1 Signaling Pathway-Mediated Autophagy. Int Arch Allergy Immunol. 2021;182(12):1245–54