2. Academic Validation
  3. Activation of IRF2 signaling networks facilitates podocyte pyroptosis in lupus nephritis

Activation of IRF2 signaling networks facilitates podocyte pyroptosis in lupus nephritis

  • Biochim Biophys Acta Mol Basis Dis. 2025 Jul 18;1871(8):167990. doi: 10.1016/j.bbadis.2025.167990.
Fan Zhang 1,  Ying Xie 2,  Ruo-Nan Dang 3,  Jie Yu 1,  Xiao-Xue Tian 4,  Lin-Jie Li 4,  Quan-Min Zhou 4,  Xiao-Min An 1,  Pei-Lei Chen 1,  Ying-Qin Luo 1,  Yuan-Sheng Wu 5,  Jun Liu 6,  Hui-Mei Zou 7
Affiliations

Affiliations

  • 1 Department of Pathophysiology, Guizhou Medical University, Guiyang, PR China; Guizhou Provincial Key Laboratory of Pathogenesis and Prevention of Common Chronic Diseases, Guizhou Medical University, Guiyang, PR China.
  • 2 Department of Pathophysiology, Guizhou Medical University, Guiyang, PR China; Guizhou Provincial Key Laboratory of Pathogenesis and Prevention of Common Chronic Diseases, Guizhou Medical University, Guiyang, PR China; Department of Dermatology, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, PR China.
  • 3 Department of Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China.
  • 4 Guizhou Provincial Key Laboratory of Pathogenesis and Prevention of Common Chronic Diseases, Guizhou Medical University, Guiyang, PR China; School of Nursing, Guizhou Medical University, Guiyang, PR China.
  • 5 Department of Dermatology, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, PR China. Electronic address: wuyuansheng007@163.com.
  • 6 Department of Rheumatology, Affiliated Hospital of Guizhou Medical University, Guiyang, PR China. Electronic address: 82541608@qq.com.
  • 7 Department of Pathophysiology, Guizhou Medical University, Guiyang, PR China; Guizhou Provincial Key Laboratory of Pathogenesis and Prevention of Common Chronic Diseases, Guizhou Medical University, Guiyang, PR China; School of Nursing, Guizhou Medical University, Guiyang, PR China. Electronic address: huimeizou@yeah.net.
PMID: 40684959 DOI: 10.1016/j.bbadis.2025.167990
Abstract

Lupus nephritis (LN), a severe and often debilitating complication of systemic lupus erythematosus (SLE), is marked by renal inflammation and structural damage. While interferon regulatory factor 2 (IRF2) has been implicated in various immune-mediated pathologies, its precise role in LN pathogenesis remains elusive. In this study, we demonstrate a significant upregulation of IRF2 in renal biopsy specimens from patients with advanced LN, as well as in the MRL/lpr murine model of LN, with expression levels correlating positively with disease severity. Genetic ablation of IRF2 in MRL/lpr mice resulted in substantial improvements in renal function, reductions in proteinuria, and attenuation of glomerular histopathological lesions, thereby underscoring a pathogenic role for IRF2 in LN progression. In vitro experiments using podocytes exposed to serum from LN patients revealed that IRF2 silencing effectively suppressed NLRP3 inflammasome activation, a key driver of Pyroptosis. Mechanistically, IRF2 exerts its effects through two primary pathways: firstly, it transcriptionally enhances the expression of critical NLRP3 inflammasome components, thereby increasing their availability for assembly; secondly, IRF2 transcriptionally represses IRBIT, leading to the release of CA2+ from the endoplasmic reticulum, a process essential for the oligomerization and activation of NLRP3 inflammasome components. By orchestrating both the expression and assembly of NLRP3 inflammasome members, IRF2 ultimately promotes podocyte Pyroptosis and accelerates LN progression. Collectively, these findings identify IRF2 as a central regulator of NLRP3 inflammasome-mediated podocyte injury in LN, suggesting novel therapeutic strategies aimed at interrupting LN pathogenesis through dual modulation of inflammatory gene networks and CA2+-dependent signaling pathways.

Keywords

Ca2+; IRF2; Lupus nephritis; NLRP3 inflammasome; Podocyte pyroptosis.

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