USP25 regulates atherosclerosis by restricting RIPK1-mediated inflammatory responses

Area of Science:

• Cardiovascular Research
• Molecular Biology
• Immunology

Background:

• Atherosclerosis is a major global health threat with incompletely understood pathogenesis.
• Deubiquitinating enzymes are implicated in various diseases, but their role in atherosclerosis requires further elucidation.

Purpose of the Study:

• To investigate the role and mechanism of USP25 in the pathogenesis of atherosclerosis.
• To identify USP25 as a potential therapeutic target for atherosclerosis.

Main Methods:

• Analysis of deubiquitinating enzyme expression in human atherosclerotic lesions.
• Validation of USP25 function in ApoE-/- mouse models.
• Mass spectrometry to identify USP25 protein substrates.
• Biochemical assays to study USP25 in signal transduction pathways.

Main Results:

• USP25 expression is significantly downregulated in human atherosclerotic lesions and predominantly in macrophages.
• Macrophagic USP25 deficiency exacerbates atherosclerosis in mice, increasing lipid deposition and inflammation.
• USP25 inhibits the NF-κB pathway in macrophages by deubiquitinating RIPK1, attenuating inflammatory responses.

Conclusions:

• USP25 plays a protective role in atherosclerosis by regulating macrophage inflammatory responses via the RIPK1/NF-κB axis.
• USP25 is identified as a beneficial regulator in atherosclerosis, offering potential for therapeutic intervention.