2. Academic Validation
  3. Identification of LDHA as a Potential Therapeutic Target for Pulmonary Hypertension Through Modulation of Endothelial-To-Mesenchymal Transition

Identification of LDHA as a Potential Therapeutic Target for Pulmonary Hypertension Through Modulation of Endothelial-To-Mesenchymal Transition

  • J Cell Mol Med. 2025 Jul;29(13):e70692. doi: 10.1111/jcmm.70692.
Maozhong Yao 1 2 3 4,  Keyan Zhong 5,  Xinbin Zheng 1 2 3 4,  Zhaoxin Yang 6,  Chunying Li 7 8,  Yong Gu 1 2 3 4,  Zhanjuan Chen 9
Affiliations

Affiliations

  • 1 Clinical Research Center, Affiliated Chinese Medicine Hospital of Hainan Medical University (Hainan Academy of Medical Sciences), Haikou, Hainan, China.
  • 2 Clinical Research Center, Hainan Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Haikou, Hainan, China.
  • 3 Hainan Clinical Center for Encephalopathy of Chinese Medicine, Haikou, Hainan, China.
  • 4 Hainan Clinical Research Center for Preventive Treatment of Diseases, Haikou, Hainan, China.
  • 5 Clinical Skills Experimental Teaching Center, Hainan Medical University (Hainan Academy of Medical Sciences), Haikou, Hainan, China.
  • 6 Research Center for Drug Safety Evaluation of Hainan Province, Hainan Medical University (Hainan Academy of Medical Sciences), Haikou, Hainan, China.
  • 7 Department of Pulmonary Diseases, Affiliated Chinese Medicine Hospital of Hainan Medical University (Hainan Academy of Medical Sciences), Haikou, Hainan, China.
  • 8 Department of Pulmonary Diseases, Hainan Hospital, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Haikou, Hainan, China.
  • 9 School of Pharmacy, Hainan Medical University (Hainan Academy of Medical Sciences), Haikou, Hainan, China.
PMID: 40629253 DOI: 10.1111/jcmm.70692
Abstract

Endothelial-to-mesenchymal transition (EndMT) induced by dysfunctional pulmonary artery endothelial cells (PAECs) is regarded as an initiating and pivotal factor in pulmonary hypertension (PH). This study focuses on identifying a novel therapeutic target for regulating EndMT in PH. A comprehensive analysis of 2 hypoxic PAECs datasets yielded 310 overlapping upregulated and 229 downregulated differentially expressed genes (DEGs). These upregulated DEGs were primarily enriched in HIF-1 signalling pathway and glycolysis/gluconeogenesis, while downregulated only in spliceosome, as indicated by KEGG. Through PPI network analysis and the application of MCC algorithms, 5 hub genes were identified among these upregulated DEGs: GAPDH, LDHA, ALDOA, PFKL, and PFKP. Their enrichment in the 2 aforementioned pathways was confirmed by cross-pathway DEGs analysis and ClueGo. Among the hub genes, LDHA was chosen as the key gene based upon expression and correlation analysis of the validation set from PH patients. Subsequent GSEA also revealed the enrichment of LDHA in these 2 pathways. Additionally, the increased expression of LDHA protein in tissues and cells was confirmed, and the elevated enzymatic activity of LDHA in clinical serum samples was also verified. From 2 online databases, 4 LDHA inhibitors were filtered out, and the stable binding between the inhibitors and the LDHA protein was confirmed through molecular docking and molecular dynamics simulation. Finally, the experimental results indicated that one of the inhibitors FX11 reversed EndMT by inhibiting the lactate-SNAI1 axis, thereby alleviating hypoxia-induced PH. The potential of LDHA as a therapeutic target for PH by modulating EndMT was proposed in this study.

Keywords

FX11; bioinformatics analysis; endothelial‐to‐mesenchymal transition; lactate dehydrogenase A; pulmonary hypertension; therapeutic target.

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