Zinc finger transcription factor ZNF384 mitigates LPS-induced ferroptosis and inflammation in lung epithelial cells by activating SESN2-mediated autophagy.

BACKGROUND

Ferroptosis, a type of programmed cell death distinct from apoptosis, is potentially associated with sepsis-triggered acute respiratory distress syndrome (ARDS). ZNF384 is a transcription factor, but its role in ARDS remain unclear.

METHODS

Blood samples were collected from sepsis-induced ARDS patients and healthy controls. BEAS-2B cells were stimulated with lipopolysaccharide (LPS) to mimic sepsis-induced damaged lung epithelial cell model. Gene and protein expression were elevated utilizing RT-qPCR, western blot, and immunofluorescent staining, respectively. Cell viability and death were evaluated by CCK-8 and flow cytometry. Inflammatory cytokines and oxidative stress markers were measured using ELISA. Intracellular ROS was determined using DCFH-DA staining. Iron concentration was measured using an iron detection kit. Target relationships were confirmed through ChIP and luciferase reporter assays.

RESULTS

ZNF384 and SESN2 levels were downregulated in sepsis-induced ARDS patients. Overexpression of ZNF384 reduced inflammatory injury, ferroptosis and enhanced autophagy in LPS-stimulated BEAS-2B cells. Mechanistically, ZNF384 served as transcriptional activator of SESN2 to boost autophagy activation. Rescue experiments validated that depletion of SESN2 strikingly reversed the regulatory function of ZNF384 in LPS-induced inflammation, autophagy and ferroptosis.

CONCLUSION

ZNF384 alleviated LPS-triggered ferroptosis and inflammation in BEAS-2B cells via activating SESN2-mediated autophagy, indicating ZNF384 was a novel target for ARDS treatment.