Clusterin protects against HFpEF by inhibiting UCHL1-mediated NLRP3 deubiquitylation and inflammasome activation

TL;DR

Clusterin reduces heart disease by blocking a harmful inflammation pathway, offering a new treatment approach for heart failure with preserved ejection fraction.

Contribution

This study identifies a novel mechanism by which Clusterin alleviates HFpEF through the UCHL1–NLRP3 signaling axis.

Findings

Clusterin overexpression improves diastolic function and reduces inflammation and fibrosis in HFpEF mice.

Clusterin inhibits UCHL1-mediated NLRP3 deubiquitylation, suppressing inflammasome activation and inflammation.

A synthetic Clusterin-derived peptide reduces cardiac fibrosis and inflammation in HFpEF mice.

Abstract

Heart failure with preserved ejection fraction (HFpEF) poses a serious threat to human health, but effective treatment strategies remain limited. Clusterin (CLU) is a multifunctional glycoprotein implicated in inflammation and tissue remodeling, but its role in HFpEF pathogenesis is not fully understood.

The effects of CLU in a murine HFpEF model were investigated by adeno-associated virus (AAV)-mediated overexpression and liver-specific knockout approaches. Cardiac function in mice was evaluated by echocardiography, and myocardial inflammation and fibrosis were assessed using Masson’s trichrome staining, real-time qPCR, and Western blot analysis. Protein interactions were identified by immunoprecipitation–mass spectrometry (IP-MS).

AAV-mediated CLU overexpression significantly improved diastolic function and reduced myocardial inflammation and fibrosis in HFpEF mice, whereas liver-specific CLU knockout aggravated disease progression. In vitro, CLU overexpression attenuated inflammatory responses and collagen production in injured cardiomyocytes. Mechanistically, CLU was found to interact with the deubiquitinase UCHL1. CLU overexpression reduced UCHL1 expression, thereby enhancing ubiquitination and degradation of NLRP3, leading to suppression of inflammasome activation and inflammation. Furthermore, treatment with a synthetic CLU-derived peptide markedly alleviated cardiac fibrosis and inflammation in HFpEF mice.

This study reveals a novel regulatory mechanism through which CLU alleviates HFpEF by modulating the UCHL1–NLRP3 signaling axis. The findings provide new insight into the anti-inflammatory and anti-fibrotic roles of CLU and suggest that CLU and its derived peptide hold translational potential as therapeutic candidates for HFpEF.

Comparison diagram depicting NLRP3 regulation in HFpEF and CLU overexpression conditions. The left side shows HFpEF with UCHL1 and NLRP3 leading to inflammasome activation, Caspase-1 generation, and IL-1β production. The right side illustrates CLU overexpression, where CLU binds UCHL1, leading to NLRP3 degradation, preventing inflammasome activation. Both scenarios are represented within a heart outline, highlighting different Ubiquitination (Ub) processes.

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