To Die or Not to Die: How Sublethal Damage Rewires Cell Fate and Implications for Sepsis

Zihan Hu, Xing Zhou, Qin Sun, Lianlian Jiang, Mengfan Wu, Jianfeng Xie, Yi Yang, Fei PengJiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Yang; Fei Peng, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, People’s Republic of China, Tel +00862583262500, Fax +00862583262500, Email yiyiyang2004@163.com; afei0312@163.comAbstract: Lytic cell death has long been regarded as an irreversible process culminating in plasma membrane rupture. However, accumulating evidence indicates that the activation of lytic pathways does not invariably result in cell lysis. Instead, cells can undergo sublethal membrane damage, a state in which membrane injury is limited, allowing cells to remain viable while triggering persistent inflammation, barrier dysfunction and other functional alterations. This potentially reversible state may provide a therapeutic window in which limiting membrane rupture or enhancing membrane repair could preserve viable but compromised cells. This review focuses on the three major forms of lytic cell death: pyroptosis, necroptosis, and ferroptosis. We summarize the canonical molecular mechanisms, processes of membrane injury, regulatory pathways, and consequences of sublethal membrane damage. Furthermore, we discuss the shared features and biological impacts of sublethal membrane damage. Given the heterogeneous responses in sepsis, sublethal membrane damage may provide a relevant framework for understanding sepsis pathophysiology. A deeper understanding of this intermediate state may offer novel strategies for sepsis that aim not only to prevent complete cell lysis but also to modulate the function of viable but compromised cells.Keywords: sepsis, lytic cell death, sublethal membrane damage, pyroptosis, necroptosis, ferroptosis