Identifying and validating potential therapeutic targets for septic heart failure and the cardioprotective effects of lycorine

Qiong Liu; Aizhen Zhao; Xiaopeng Wu; Xin Zhang; Xiaoru Li; Wenwen Yang; Wangrui Lei; Hui Liu; Huadong Zhao; Shuai Jiang; Yang Yang; Mingzhi Shen

doi:10.1016/j.phymed.2024.155677

Identifying and validating potential therapeutic targets for septic heart failure and the cardioprotective effects of lycorine

Phytomedicine. 2024 Apr 23:129:155677. doi: 10.1016/j.phymed.2024.155677. Online ahead of print.

Authors

Qiong Liu¹, Aizhen Zhao¹, Xiaopeng Wu¹, Xin Zhang¹, Xiaoru Li¹, Wenwen Yang¹, Wangrui Lei¹, Hui Liu¹, Huadong Zhao², Shuai Jiang³, Yang Yang⁴, Mingzhi Shen⁵

Affiliations

¹ Xi'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.
² Department of General Surgery, Tangdu Hospital, The Airforce Medical University, Xi'an, 710038, China.
³ Department of Aerospace Hygiene, The Air Force Medical University, Xi'an, 710032, China.
⁴ Xi'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. Electronic address: yang200214yy@nwu.edu.cn.
⁵ Department of General Medicine, Hainan Hospital of Chinese People's Liberation Army (PLA) General Hospital, Sanya, 572013, China. Electronic address: mingzhishenhainan@163.com.

PMID: 38678951
DOI: 10.1016/j.phymed.2024.155677

Abstract

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.

Keywords: BCL3; Herat failure; Lycorine; Sepsis; WGCNA.