Citation: Yue Xu, Lingzhi Wang, Liu Yang, Renliang Xue, Haowen Zhu, Qifeng Liu, Xueqi Lv, Ruiping Zhang, Jun Tu, Qingce Zang, Yinghong Wang. Spatial metabolomics combined with transcriptomics to reveal heterogeneous metabolism and drug response in the heart of rats with heart failure[J]. Chinese Chemical Letters, ;2025, 36(7): 110958. doi: 10.1016/j.cclet.2025.110958 shu

Spatial metabolomics combined with transcriptomics to reveal heterogeneous metabolism and drug response in the heart of rats with heart failure

Yue Xu ^{a, 1} ,
Lingzhi Wang ^{a, 1} ,
Liu Yang ^a ,
Renliang Xue ^a ,
Haowen Zhu ^a ,
Qifeng Liu ^{a, b} ,
Xueqi Lv ^a ,
Ruiping Zhang ^a ,
Jun Tu ^{c, *,} ,
Qingce Zang ^{a, *,} ,
Yinghong Wang ^{a, *,}

a.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
b.
Core Facility, West China Hospital, Sichuan University, Chengdu 610041, China
c.
Research Center for Differentiation and Development of TCM Basic Theory & Jiangxi Province Key Laboratory of TCM Etiopathogenesis, Jiangxi University of Chinese Medicine, Nanchang 330004, China

Juntu@jxutcm.edu.cn

zangqingce@imm.ac.cn

wyh@imm.ac.cn

Received Date: 27 August 2024
Revised Date: 18 January 2025
Accepted Date: 13 February 2025
Available Online: 15 February 2025

Figures(4)

A comprehensive understanding of the molecular details at spatial levels within heterogeneous cardiac tissue in heart failure (HF) is paramount for enhancing our knowledge of the pathophysiology of HF and pinpointing potential therapeutic targets. Here, we present an analytical strategy for the deep discovery of heterogeneous metabolism and drug response in the heart tissue of rats with HF using airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) coupled with bulk RNA sequencing. Spatial metabolomics illustrated pronounced metabolic heterogeneity between the infarct (Ⅰ), infarct margin (IM), and non-infarct (NI) areas of heart tissue in HF. Integrated transcriptomics showed that increased mRNA expression of ATP citrate lyase disrupted the tricarboxylic acid (TCA) cycle in the NI area. Impairment of the carnitine shuttle system led to a significant accumulation of carnitines, suggesting potential abnormalities in fatty acid (FA) oxidation. Coupling on-tissue chemical derivatization with AFADESI-MSI enabled us to confirm the occurrence of incomplete oxidation of FAs in the NI area. Additionally, we observed a heterogeneous drug response between the anti-HF medications valsartan and Qishen Yiqi Dripping Pills (QDP). Valsartan exhibited a more pronounced effect on metabolic regulation in the Ⅰ area, whereas QDP exerted stronger regulatory effects on metabolism in the NI area. Utilizing this method, four potential therapeutic targets were identified in HF: CPT1A, PDHB, ACLY, and BCAT2, which were preliminarily validated by western blotting. Overall, integrating spatial metabolomics with transcriptomics facilitates comprehensive analyses that link differential metabolites and genes, enabling a more precise characterization of metabolic changes in heart injury microareas and providing effective methods for elucidating molecular mechanisms and identifying potential therapeutic targets for HF.
- Spatial metabolomics,
- Transcriptomics,
- On-tissue chemical derivatization,
- Metabolic remodeling,
- Heart failure
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