NAT10-mediated ac4C acetylation of TFRC promotes sepsis-induced pulmonary injury through regulating ferroptosis

• Published in: Molecular medicine (Cambridge, Mass.) Vol. 30; no. 1; pp. 140 - 11
• Main Authors: Xing, Pengcheng, Zhou, Minjie, Sun, Jian, Wang, Donglian, Huang, Weipeng, An, Peng
• Format: Journal Article
• Language: English
• Published: London BioMed Central 09.09.2024; BMC
• Subjects: Ac4C; Ferroptosis; NAT10; Sepsis-induced pulmonary injury; TFRC
• ISSN: 1528-3658; 1076-1551; 1528-3658
• DOI: 10.1186/s10020-024-00912-w

Abstract Background Sepsis-induced pulmonary injury (SPI) is a common complication of sepsis with a high rate of mortality. N4-acetylcytidine (ac 4 C) is mediated by the ac 4 C “writer”, N-acetyltransferase (NAT)10, to regulate the stabilization of mRNA. This study aimed to investigate the role of NAT10 in SPI and the underlying mechanism. Methods Twenty-three acute respiratory distress syndrome (ARDS) patients and 27 non-ARDS volunteers were recruited. A sepsis rat model was established. Reverse transcription-quantitative polymerase chain reaction was used to detect the expression of NAT10 and transferrin receptor (TFRC). Cell viability was detected by cell counting kit-8. The levels of Fe 2+ , glutathione, and malondialdehyde were assessed by commercial kits. Lipid reactive oxygen species production was measured by flow cytometric analysis. Western blot was used to detect ferroptosis-related protein levels. Haematoxylin & eosin staining was performed to observe the pulmonary pathological symptoms. Results The results showed that NAT10 was increased in ARDS patients and lipopolysaccharide-treated human lung microvascular endothelial cell line-5a (HULEC-5a) cells. NAT10 inhibition increased cell viability and decreased ferroptosis in HULEC-5a cells. TFRC was a downstream regulatory target of NAT10-mediated ac 4 C acetylation. Overexpression of TFRC decreased cell viability and promoted ferroptosis. In in vivo study, NAT10 inhibition alleviated SPI. Conclusion NAT10-mediated ac 4 C acetylation of TFRC aggravated SPI through promoting ferroptosis. Graphical Abstract