HO-1 alleviates lipopolysaccharide-induced acute lung injury in mice by downregulating TFE3 expression and nuclear translocation and suppressing Golgi stress response.

Sepsis-induced acute lung injury (ALI) is associated with increased morbidity and mortality rates in the intensive care unit. Transcription factor E3(TFE3) is reported to drive inflammation and Golgi stress response in some pathological conditions. However, the functions and regulatory mechanisms of TFE3 in ALI have not been elucidated. This study demonstrated that lipopolysaccharide (LPS)-induced TFE3 expression and nuclear translocation promoted Golgi stress response and inflammatory cytokine upregulation and exacerbated septic lung injury in vivo and in vitro. The knockdown or knockout of Tfe3 alleviated ALI by downregulating Golgi stress response, inflammatory cytokines, and reactive oxygen species. Meanwhile, the knockout or knockdown of Hmox1 promoted TFE3 nuclear translocation, dysregulating the expression of Golgi stress response-related proteins and exacerbating sepsis induced ALI in vivo and in vitro. Thus, TFE3 exacerbates inflammation, apoptosis, and oxidative stress and induces Golgi stress response in sepsis-induced ALI. Additionally, HO-1 exerted protective effects against ALI by downregulating TFE3 expression and nuclear translocation and suppressing Golgi stress response. The regulatory mechanism of HO-1 in the TFE3/Golgi stress response signaling pathway can be a potential therapeutic target for ALI.