Qiancheng Xu,1,* Yan Qian,2,* Yingya Cao,1 Weihua Lu,1 Jianguo Li3 

1Department of Critical Care Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, 241000, People’s Republic of China; 2Department of Emergency Intensive Care Unit, Wuhu Hospital, East China Normal University, Wuhu, Anhui, 241000, People’s Republic of China; 3Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Jianguo Li, Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China, Email drljg5361@163.com Weihua Lu Department of Critical Care Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, 241000, People’s Republic of China, Email lwh683@126.com

Abstract: Sepsis-associated acute lung injury (ALI) is a leading cause of death in sepsis patients, characterized by complex pathogenesis involving inflammatory responses, immune dysregulation, cell death, and coagulation system activation. Despite advancements in critical care, specific drugs or therapies for ALI remain unavailable. Pannexin 1 (Panx1), a widely expressed membrane channel protein, has emerged as a pivotal regulator in the onset and progression of sepsis-induced ALI. During the early stages, Panx1 amplifies inflammatory responses by promoting immune cell activation, chemotaxis, cytokine release, and coagulation. Simultaneously, it contributes to epithelial and endothelial cell damage through apoptosis, pyroptosis, and ferroptosis. Conversely, in the recovery phase, Panx1 plays a reparative role, facilitating inflammation resolution, epithelial cell proliferation, and tissue regeneration. This review highlights Panx1’s dual role, presenting it as a promising therapeutic target. Preclinical models have demonstrated a key therapeutic advantage: the potential for stage-specific interventions. This strategy involves pharmacological inhibition to mitigate early-stage damage and potential activation to promote later-stage repair. However, a critical knowledge gap remains in defining the precise therapeutic window for such interventions and translating these findings into clinical practice. By elucidating Panx1’s complex mechanisms, we aim to provide a theoretical basis for novel therapeutic strategies, addressing a critical unmet need in sepsis-induced ALI management and improving patient outcomes.

Keywords: pannexin 1, ATP, sepsis, acute lung injury, inflammation, cell death