Background The heterogeneous etiology and limited therapeutic options of pediatric restrictive cardiomyopathy (RCM)underscore the urgent need to elucidate its molecular mechanisms and identify potential treatment targets. Methods We performed integrated transcriptomic and proteomic analyses on myocardial tissues from 7 pediatric RCM patients and 3 control donors. Differentially expressed genes (DEG) were detected, with log2 transformed fold change (log2FC)>1 or log2FC < -1 as well as P < 0.05 after the correction of false discovery rates (FDR) as the threshold. Then, the same proteins as DEGs were identified from the proteomic profiling for the further analysis. The t-test was adopted and the differentially expressed proteins (DEPs) with P < 0.05 after FDR correction and an FC > 1.5 or <0.67 were labeled as significant dysregulation. Furthermore, pathway enrichment was further conducted based on DEGs and DEPs, respectively. RNA and protein validation studies (including real-time polymerase chain reaction and western blot) were conducted to confirm key molecular alterations. Finally, bioinformatic approaches were employed to predict potential therapeutic candidates targeting the identified pathways. Results Multi-omics integration revealed 23 consistently dysregulated genes/proteins central to RCM pathogenesis (FDR adjusted P < 0.05). RNA validation confirmed significant expression changes in most hub genes, while protein-level assays demonstrated marked downregulation of CKB, PGAM2, and TPM2 in RCM myocardium (P < 0.05). Functional enrichment analysis highlighted the involvement of these molecules in critical pathways, including muscle contraction, sarcomere organization, and extracellular matrix remodeling. Drug prediction analysis identified several repurposed candidates, including phenytoin, diazepam, and paricalcitol, which may target these aberrant pathways. Conclusions This study elucidates the fundamental molecular mechanisms underlying muscle contraction and energy metabolism in RCM, while simultaneously translating these insights into clinically actionable strategies. Specifically, it identifies the downregulation of key proteins as potential biomarkers and proposes drug repurposing strategies informed by pathway analysis. These findings offer a novel perspective on the pathophysiology of RCM and establish an evidence-based foundation for the development of targeted diagnostic and therapeutic tools. Impact <UnorderedList Mark="Bullet"> <ItemContent> This study offers a novel perspective on the mechanisms underlying pediatric primary restrictive cardiomyopathy, specifically highlighting abnormalities in muscle regulation and the myocardial extracellular matrix. Additionally, the predicted therapeutic targets for pediatric primary restrictive cardiomyopathy indicate the new directions for their clinical management except for the treatment of advanced heart failure. </ItemContent> </UnorderedList>

Integrated transcriptomics and proteomics analysis reveal potential target in pediatric primary restrictive cardiomyopathy

期刊论文
发表日期：

2026年3月24日

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Xihang Fu,
Jie Liu,
Qing Guo,
Lin Wang,
Jing Wu,
Zubo Wu,
Yanlin Xing,
Peng Zhu,
Nianguo Dong,
Jiawei Shi,
Hua Peng

摘要

Background

The heterogeneous etiology and limited therapeutic options of pediatric restrictive cardiomyopathy (RCM)underscore the urgent need to elucidate its molecular mechanisms and identify potential treatment targets.

Methods

We performed integrated transcriptomic and proteomic analyses on myocardial tissues from 7 pediatric RCM patients and 3 control donors. Differentially expressed genes (DEG) were detected, with log₂ transformed fold change (log2FC)>1 or log2FC < -1 as well as P < 0.05 after the correction of false discovery rates (FDR) as the threshold. Then, the same proteins as DEGs were identified from the proteomic profiling for the further analysis. The t-test was adopted and the differentially expressed proteins (DEPs) with P < 0.05 after FDR correction and an FC > 1.5 or <0.67 were labeled as significant dysregulation. Furthermore, pathway enrichment was further conducted based on DEGs and DEPs, respectively. RNA and protein validation studies (including real-time polymerase chain reaction and western blot) were conducted to confirm key molecular alterations. Finally, bioinformatic approaches were employed to predict potential therapeutic candidates targeting the identified pathways.

Results

Multi-omics integration revealed 23 consistently dysregulated genes/proteins central to RCM pathogenesis (FDR adjusted P < 0.05). RNA validation confirmed significant expression changes in most hub genes, while protein-level assays demonstrated marked downregulation of CKB, PGAM2, and TPM2 in RCM myocardium (P < 0.05). Functional enrichment analysis highlighted the involvement of these molecules in critical pathways, including muscle contraction, sarcomere organization, and extracellular matrix remodeling. Drug prediction analysis identified several repurposed candidates, including phenytoin, diazepam, and paricalcitol, which may target these aberrant pathways.

Conclusions

This study elucidates the fundamental molecular mechanisms underlying muscle contraction and energy metabolism in RCM, while simultaneously translating these insights into clinically actionable strategies. Specifically, it identifies the downregulation of key proteins as potential biomarkers and proposes drug repurposing strategies informed by pathway analysis. These findings offer a novel perspective on the pathophysiology of RCM and establish an evidence-based foundation for the development of targeted diagnostic and therapeutic tools.

Impact

This study offers a novel perspective on the mechanisms underlying pediatric primary restrictive cardiomyopathy, specifically highlighting abnormalities in muscle regulation and the myocardial extracellular matrix. Additionally, the predicted therapeutic targets for pediatric primary restrictive cardiomyopathy indicate the new directions for their clinical management except for the treatment of advanced heart failure.