2. Academic Validation
  3. Red blood cells undergo lytic programmed cell death involving NLRP3

Red blood cells undergo lytic programmed cell death involving NLRP3

  • Cell. 2025 May 29;188(11):3013-3029.e19. doi: 10.1016/j.cell.2025.03.039.
Yaozhen Chen 1,  Shouwen Chen 2,  Zhixin Liu 1,  Yafen Wang 1,  Ning An 1,  Yutong Chen 1,  Yihao Peng 3,  Zheng Liu 3,  Qin Liu 4,  Xingbin Hu 5
Affiliations

Affiliations

  • 1 Department of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi, China.
  • 2 State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, East China University of Science and Technology, Shanghai 200237, China. Electronic address: swchen@ecust.edu.cn.
  • 3 Kobilka Institute of Innovative Drug Discovery, School of Medicine, Chinese University of Hong Kong, Shenzhen 518115, Guangdong, China.
  • 4 State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, East China University of Science and Technology, Shanghai 200237, China. Electronic address: qinliu@ecust.edu.cn.
  • 5 Department of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi, China. Electronic address: hxbyqh@fmmu.edu.cn.
PMID: 40252640 DOI: 10.1016/j.cell.2025.03.039
Abstract

The canonical complement-mediated lysis of mature red blood cells (RBCs) leads to severe pathogenesis. However, inhibition strategies targeting complement are not always as efficient as expected, indicating that unknown mechanisms are awaiting elucidation. In this study, we investigate the intracellular events in mature RBCs following complement activation. The collected evidence demonstrates that complement-induced hemolysis is a caspase-8-dependent programmed RBC death. Furthermore, short NLRP3 (miniNLRP3) fragments in RBCs are identified to engage in the assembly of NLRP3-apoptosis-associated speck-like protein containing a CARD (ASC)-caspase-8 complex. Activated Caspase-8 directly induces the proteolysis of β-spectrin, thereby disrupting the skeletal network of the RBC membrane, a process we refer to as spectosis. Spectosis signaling is also activated in autoimmune hemolytic anemia or paroxysmal nocturnal hemoglobinuria, and the inhibition of spectosis significantly reduced complement-induced hemolysis. These findings reveal a programmed death cascade in mature RBCs, which may have important implications for the treatment of hemolytic disorders.

Keywords

NLRP3; caspase-8; complement; hemolysis; programmed cell death; red blood cells; spectrin.

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