Inhibition of myocardial ferroptosis ameliorates sepsis-induced cardiomyopathy
Kuangyang Yang, Jing Wang, Zhaocong Yang, Yingzhi Zhou, Liangming Liu, Chunhua MaAbstract
Background
The mechanisms of sepsis-induced cardiomyopathy (SIC) and preferable treatment methods remain unclear. The aim of this study was to explore new found mechanisms and treatment methods for SIC.
Methods
Proteomics was used to detect serum differential proteins in healthy individuals (Control) and patients with sepsis-induced cardiomyopathy (SIC). Single-cell sequencing was used to examine USP10 expression in the cardiac tissue of SIC mice. Specifically, USP10 was knocked down in cardiac macrophages to evaluate the mechanism through which USP10 affects ferroptosis in SIC and identify its downstream genes. Further validation of the interaction between USP10 and NRF1 was performed through luciferase reporter genes, and the deubiquitination of NRF1 by USP10 was detected by Western blotting. Mannitol and myocardial targeting peptide (CSTSMLKAC, CTP)-modified ZIF-90 loaded with a USP10 overexpression lentivirus (AAV) and ferroptosis inhibitor ferrostatin-1 (Fer-1) (MCZFA) were prepared to target myocardial macrophages to inhibit ferroptosis.
Results
Proteomics results and single-cell sequencing revealed that USP10 expression was significantly decreased in SIC and that USP10 was expressed mainly in cardiac macrophages. Macrophage-specific knockout of USP10 exacerbated ferroptosis in SIC. RNA sequencing and luciferase reporter gene assays revealed NRF1 to be the most important regulatory target of USP10. USP10 is also a deubiquitinate of NRF1, which can directly interact with NRF1 and deubiquitinate NRF1 in an enzyme activity–dependent manner, and USP10 inhibits ferroptosis in SIC by stabilizing NRF1. MCZFA double targeted cardiac macrophages to inhibit ferroptosis and ameliorate SIC.
Conclusion
The results of the present study revealed that USP10 exerted protective effects on SIC through the deubiquitination of NRF1. MCZFA, which targeted the inhibition of ferroptosis to alleviate SIC, was also developed.