Crosstalk Between Cell Death and the cGAS-STING Pathway in Sepsis-Associated Acute Lung Injury

Sepsis-associated acute lung injury (ALI) is a complex pathological condition characterized by dysregulated inflammatory responses and the activation of various cell death mechanisms. This review examines the interplay between cell death pathways and the cGAS-STING signaling pathway in sepsis-associated ALI. The cGAS-STING pathway, which recognizes pathogen-derived DNA to trigger innate immune responses, can exacerbate lung injury when dysregulated. Recent studies have revealed that apoptosis, pyroptosis, necroptosis, autophagy, ferroptosis, NETosis, and PANoptosis are all intricately linked to the cGAS-STING pathway. These cell death mechanisms interact synergistically to amplify inflammation and tissue damage. Targeting the cGAS-STING pathway has been shown to reduce both inflammation and cell death in sepsis-associated ALI. For instance, inhibiting the stimulator of interferon genes (STING) pathway can mitigate ferroptosis and inflammation in macrophages, suggesting its potential as a therapeutic target. Furthermore, exosome-based therapies that modulate immune responses and promote tissue repair are emerging as promising strategies for treating ALI. However, further research is needed to fully elucidate the specific mechanisms through which the cGAS-STING pathway regulates cell death and inflammation in ALI. Additionally, exploring combination therapies that integrate STING inhibitors with other treatments, such as anti-inflammatory agents, may offer improved clinical outcomes in sepsis-associated ALI.