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PLCB3 as a causal regulator linking ferroptosis and immune remodeling in heart failure with preserved ejection
Huiling Zhu1, Chaofan Qin2, Jiejie Yang1
1Department of Cardiovascular Medicine, Cardiovascular Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016,China.
Background:
Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome lacking effective targeted therapies, but its causal genes and mechanisms remain poorly defined.
Objective:
To investigate the role of PLCB3 and its association with ferroptosis in HFpEF.
Methods:
We integrated transcriptomic data and genome-wide association studies (GWAS) data and employed differential expression analysis, mendelian randomization (MR), summary data-based mendelian randomization (SMR), and colocalization analysis to identify key genes associated with HFpEF. Furthermore, functional validation was performed using a HFpEF mouse model and siRNA mediated PLCB3 knockdown in AC16 cardiomyocytes. Cell viability, reactive oxygen species (ROS), lipid peroxidation, and ferroptosis related protein expression were subsequently assessed to investigate the molecular mechanisms underlying PLCB3-mediated ferroptosis.
Results:
Phospholipase C beta 3 (PLCB3) was identified as a candidate causal gene for HFpEF. PLCB3 expression was significantly reduced in HFpEF cardiac tissue and a mouse model induced by high-fat diet and L-NAME. Knockdown of PLCB3 decreased cell viability and induced ferroptosis, as indicated by reduced GPX4 and FTH1 expression, increased ACSL4 levels, and elevated lipid peroxidation and reactive oxygen species. These effects were significantly reversed by the ferroptosis inhibitor Ferrostatin-1. In vivo, ferroptosis-related markers were similarly altered in HFpEF mice. In addition, immune infiltration analysis revealed significant differences in multiple immune cell populations between HFpEF and controls. Single-cell eQTL-based MR analysis further suggested that PLCB3 expression is associated with specific immune cell subsets, including B cells, CD4+ naïve T cells, and natural killer cells.
Conclusion:
PLCB3 is a potential regulator of HFpEF and may contribute to disease progression by promoting ferroptosis and immune alterations. These findings provide new insights into the molecular mechanisms of HFpEF and suggest that targeting PLCB3 may represent a novel therapeutic strategy.
