TIPE2 Alleviates Sepsis-induced Lung Injury By Inhibiting PANoptosis in Murine Alveolar Macrophages

Sepsis-induced acute lung injury (ALI) is a life-threatening condition with high mortality rates, and its underlying mechanisms remain poorly understood. This study investigates the role of TNF-α-induced protein 8-like 2 (TIPE2) in modulating PANoptosis, an integrated form of programmed cell death that includes apoptosis, necroptosis, and pyroptosis, in the context of sepsis-induced lung injury. We utilized a cecal ligation and puncture (CLP) mouse model to examine the effects of TIPE2 knockout and overexpression on lung injury, inflammation, and cell death pathways. Our findings demonstrate that TIPE2 knockout exacerbates lung injury by promoting the abnormal activation of PANoptosis-related proteins, leading to increased inflammation and tissue damage. In contrast, overexpression of TIPE2 in macrophages significantly reduces these effects by inhibiting the ZBP1-dependent PANoptosis pathway via TRIF signaling. These results highlight the crucial role of TIPE2 in maintaining the balance between cell survival and death during sepsis and suggest that targeting TIPE2 could be a novel therapeutic strategy for treating sepsis-related lung injury.