Serum HMGB-1 released by ferroptosis and necroptosis as a novel potential biomarker for systemic lupus erythematosus

Abstract

• SLE is autoimmune and inflammatory disease with numerous serological immunological hallmarks, but the inflammatory hallmark is lack. • This study firstly identified HMGB-1 as a shared executioner of PCDs and served as an inflammatory biomarker for the disease. • This work demonstrated the potential relationships between necroptosis and ferroptosis. High mobility group box proterin-1 (HMGB-1) is a multifunctional protein that can be released by various programmed cell deaths (PCDs), such as necroptosis and ferroptosis. PCDs play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). However, the role of HMGB-1 in the process of SLE remains unclear. This study aims to demonstrate the potential diagnosing role of serum HMGB-1 in SLE that released by necroptosis and ferroptosis. We found that the serum levels of HMGB-1, receptor-interacting protein kinase 3 (RIPK3) /mixed lineage kinase domain-like protein (MLKL) related with necroptosis, and metabolites associated with ferroptosis were significantly upregulated in SLE patients compared to HC individuals. These serum levels were positively correlated with SLE disease activity. Additionally, the serum level of HMGB-1 showed a strong positive correlated with the levels of RIPK3/MLKL and ferroptosis metabolites. Moreover, the serum level of HMGB-1 was correlated with renal involvement and high-antinuclear antibodies (ANA) titer. After SLE serum and interferon γ (IFN-γ) treatment in vitro , the level of necroptosis and ferroptosis markers were activated and HMGB1 was released both in HEK293 and HK2 cells. Clinically, HMGB-1 was considered as a significant independent risk factor in SLE serum by binary logistic assay. Notably, HMGB-1 exhibited outstanding diagnostic ability for SLE by the area under the curve (AUC) in receiver operating characteristic (ROC) curve analysis. Taken together, our study indicates that the serum level of HMGB-1 is a promising biomarker for the diagnosis and monitoring of SLE.