Integrative bioinformatics and machine learning combined with experimental validation in a doxorubicin-induced model identify BACH2, NXPH4, CD1E, and LIF as sodium overload-related molecular signatures in dilated cardiomyopathy

  • Life Sci. 2026 May 1:392:124294. doi: 10.1016/j.lfs.2026.124294.
Shuai Xu  1 ,  Wei Yu  1 ,  Bin Ma  2 ,  Anchen Xu  1 ,  Yiyao Zeng  3 ,  Xin Tan  1 ,  Xiangyu Wang  1 ,  Huimin Fan  4 ,  Yuxin Nong  1 ,  Hangyao Zhang  1 ,  Ziliang Chen  1 ,  Yufeng Jiang  5 ,  Yahui Song  6 ,  Yafeng Zhou  7
Affiliations
  • 1. Department of Cardiology, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215000, China; Institute for Hypertension, Soochow University, Suzhou, 215000, China.
  • 2. Department of General Practice, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215000, China.
  • 3. Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 4. Center of Translational Medicine and Clinical Laboratory, The Fourth Affiliated Hospital to Soochow University, Suzhou, 215028, China.
  • 5. Department of Cardiology, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215000, China; Institute for Hypertension, Soochow University, Suzhou, 215000, China. Electronic address: [email protected].
  • 6. Center of Translational Medicine and Clinical Laboratory, The Fourth Affiliated Hospital to Soochow University, Suzhou, 215028, China. Electronic address: [email protected].
  • 7. Department of Cardiology, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215000, China; Institute for Hypertension, Soochow University, Suzhou, 215000, China. Electronic address: [email protected].
PMID: 41747960 DOI: 10.1016/j.lfs.2026.124294
Abstract

Introduction: Dilated cardiomyopathy (DCM) is a leading cause of heart failure and remains a major clinical challenge due to its complex etiology and lack of effective targeted therapies. Sodium overload-induced necrosis, a recently described form of regulated cell death, has emerged as a novel contributor to cardiovascular injury, but its role in DCM remains poorly defined.

Aims: This study aimed to elucidate the molecular signatures of sodium overload-associated cell death and explore their diagnostic and therapeutic relevance in DCM.

Materials and methods: We systematically integrated four publicly available transcriptomic datasets (GSE226801, GSE116250, and GSE141910) from human myocardial tissues and in vitro sodium-overload models to identify sodium overload-associated death-related genes (DRGs). Machine learning algorithms were used to screen and validate key hub genes. Experimental validation was performed in a doxorubicin-induced DCM mouse model using Western blotting, quantitative PCR, and immunohistochemistry. Drug-gene interaction analysis was conducted using the Comparative Toxicogenomics Database (CTD).

Key findings: Four hub genes-BACH2, NXPH4, CD1e, and LIF-were identified as central regulators linking sodium overload to DCM pathogenesis. A diagnostic model incorporating these genes showed robust discrimination between DCM patients and healthy controls across multiple datasets. Furthermore, abrine was identified through CTD analysis as a potential therapeutic candidate capable of simultaneously targeting all four hub genes.

Significance: This study uncovers a novel mechanistic link between sodium overload-induced regulated necrosis and DCM progression. The findings provide new molecular insights into cardiomyocyte death and inflammation in DCM and propose candidate biomarkers and drug targets for precision therapy.

Keywords
Biomarkers; Cell Death; Dilated cardiomyopathy; Sodium Overload; Therapeutic.
Products