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Identifying and validating potential therapeutic targets for septic heart failure and the cardioprotective effects of
Qiong Liu1, Aizhen Zhao1, Xiaopeng Wu1
1Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Northwest University First Hospital, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, 710069, China.
Insights
Lycorine (LYC) protects against septic heart failure by inhibiting the BCL3 gene. This study identifies BCL3 as a key target, offering a new therapeutic strategy for sepsis management.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Bioinformatics
Background:
- Septic heart failure remains a significant clinical challenge.
- Lycorine (LYC) has shown potential in treating sepsis and septic myocardial injury.
- Further research is needed to understand LYC's molecular mechanisms in sepsis.
Purpose of the Study:
- To investigate the protective effects and underlying mechanisms of lycorine (LYC) in a mouse model of sepsis-induced heart failure.
- To identify key genes and pathways involved in LYC's therapeutic action using bioinformatics and experimental validation.
Main Methods:
- Transcriptome analysis to identify differentially expressed genes (DEGs) after LYC treatment.
- Weighted gene co-expression network analysis (WGCNA) to identify key gene modules and hub genes.
- In vivo and in vitro experiments to validate the role of BCL3 in LYC's protective effects.
Main Results:
- Transcriptome and WGCNA analyses identified BCL3 as a core gene associated with LYC's protective effects.
- BCL3 expression was negatively correlated with cardiac function indicators.
- LYC protected against septic myocardial injury by inhibiting BCL3; BCL3 knockdown ameliorated injury, while overexpression reversed LYC's protective effects.
Conclusions:
- Lycorine (LYC) significantly attenuates septic myocardial disorder by targeting the BCL3 gene.
- This study is the first to report BCL3's role in sepsis and septic myocardial injury.
- Findings suggest LYC as a potential adjunctive therapy for septic heart failure, with BCL3 as a novel therapeutic target.
Background:
Septic heart failure has been recognized as a puzzle since antiquity and poses a major challenge to modern medicine. Our previous work has demonstrated the potential effects of lycorine (LYC) on sepsis and septic myocardial injury. Nonetheless, further exploration is needed to elucidate the underlying cellular and molecular mechanisms.
Methods:
In this study, we conducted transcriptome analysis and weighted gene co-expression network analysis (WGCNA) to identify the key genes and reveal the mechanism of LYC against septic heart failure.
Purpose:
This study aims to apply bioinformatic analysis and experimental validations to explore the protective effects and underlying mechanism of LYC on the cecal ligation and puncture (CLP)-induced sepsis model mice.
Results:
Transcriptome analysis revealed the differentially expressed genes (DEGs) following LYC treatment. WGCNA analysis identified gene modules associated with LYC-mediated protection, with BCL3 emerging as a core gene within these modules. Notably, BCL3 was an overlapping gene of DEGs and WGCNA core genes induced by LYC treatment, and is highly negatively correlated with cardiac function indicator. In vivo and in vitro study further prove that LYC exerted a protective effect against septic myocardial injury through inhibiting BCL3. BCL3 siRNA ameliorated LPS-induced cardiac injury and inflammation, while BCL3 overexpression reversed the protective effect of LYC against LPS injury.
Conclusion:
In summary, our findings demonstrate the significant attenuation of septic myocardial disorder by LYC, with the identification of BCL3 as a pivotal target gene. This study is the first to report the role of BCL3 in sepsis and septic myocardial injury. Furthermore, the strategy for hub genes screening used in our study facilitates a comprehensive exploration of septic targets and reveals the potential targets for LYC effect. These findings may offer a new therapeutic strategy for the management of septic heart failure, highlighting the cardioprotective effect of LYC as adjunctive therapy for sepsis management.
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