Spermidine attenuates monocrotaline-induced pulmonary arterial hypertension with HADHA-associated improvements in fatty acid oxidation and mitochondrial redox homeostasis
- 1Yu-Yue Pathology Scientific Research Center, Jinfeng Laboratory, Chongqing, 400039, China
- 2Institute of Medicine and Equipment for High Altitude Region, College of High Altitude Military Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China; Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Army Medical University (Third Military Medical University), Chongqing, 400038, China
Abstract
Metabolic reprogramming, impaired mitochondrial quality control, and mitochondrial redox imbalance are increasingly recognized as central drivers of pulmonary arterial hypertension (PAH). Spermidine (SPD) has been reported to exert cardiovascular protective effects; however, its effects on endothelial metabolism and redox homeostasis in PAH remain incompletely characterized. HADHA, the α-subunit of mitochondrial trifunctional protein, participates in long-chain fatty acid β-oxidation (FAO) and provides a potential link between fatty acid utilization, mitochondrial respiration, mitophagy-related quality control, and redox homeostasis. Here, using integrated metabolomics, lipidomics, and molecular biology approaches in monocrotaline (MCT)-induced PAH rats and palmitic acid-stimulated pulmonary microvascular endothelial cells (PMVECs), we examined the contribution of HADHA to the effects of SPD on endothelial FAO and mitochondrial redox homeostasis. SPD treatment markedly attenuated pulmonary hypertension and vascular remodeling, accompanied by reduced inflammatory activation and endothelial injury. Metabolomic and lipidomic profiling indicated that SPD partially corrected pathological lipid-metabolic remodeling, including phosphatidylethanolamine-associated lipid alterations, and improved FAO-related mitochondrial function under lipotoxic stress. SPD reduced lipid accumulation and lipotoxic mitochondrial injury, inhibited PLIN2-vimentin-associated endothelial-to-mesenchymal transition (EndMT) marker changes, and increased PINK1/Parkin-related mitophagy markers together with TOM20/LC3B/LAMP2 colocalization, consistent with improved mitophagy-related mitochondrial quality control. Molecular dynamics simulation, cellular thermal shift assay, and microscale thermophoresis supported SPD-HADHA binding and SPD-associated HADHA stabilization. Importantly, HADHA knockdown markedly attenuated several effects of SPD on FAO-related function, mitochondrial redox balance, and lipotoxic phenotypes in PMVECs. These findings suggest that HADHA may contribute to the effects of SPD on fatty acid oxidation, redox homeostasis, and endothelial protection in PAH.
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BibTeX
@article{bai2026spermidine,
title = {{Spermidine attenuates monocrotaline-induced pulmonary arterial hypertension with HADHA-associated improvements in fatty acid oxidation and mitochondrial redox homeostasis}},
author = {Xinyu Bai and Keke Tian and Shiyuan Song and Xiuming Rao and Gang Xu and Erlong Zhang and Bao Liu and Yan Wang and Yuqi Gao},
journal = {Redox Biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104392},
url = {https://doi.org/10.1016/j.redox.2026.104392},
note = {CC BY},
}
RIS
TY - JOUR
TI - Spermidine attenuates monocrotaline-induced pulmonary arterial hypertension with HADHA-associated improvements in fatty acid oxidation and mitochondrial redox homeostasis
AU - Xinyu Bai
AU - Keke Tian
AU - Shiyuan Song
AU - Xiuming Rao
AU - Gang Xu
AU - Erlong Zhang
AU - Bao Liu
AU - Yan Wang
AU - Yuqi Gao
PY - 2026
DA - 2026/10/30
JO - Redox Biology
DO - 10.1016/j.redox.2026.104392
UR - https://doi.org/10.1016/j.redox.2026.104392
AB - Metabolic reprogramming, impaired mitochondrial quality control, and mitochondrial redox imbalance are increasingly recognized as central drivers of pulmonary arterial hypertension (PAH). Spermidine (SPD) has been reported to exert cardiovascular protective effects; however, its effects on endothelial metabolism and redox homeostasis in PAH remain incompletely characterized. HADHA, the α-subunit of mitochondrial trifunctional protein, participates in long-chain fatty acid β-oxidation (FAO) and provides a potential link between fatty acid utilization, mitochondrial respiration, mitophagy-related quality control, and redox homeostasis. Here, using integrated metabolomics, lipidomics, and molecular biology approaches in monocrotaline (MCT)-induced PAH rats and palmitic acid-stimulated pulmonary microvascular endothelial cells (PMVECs), we examined the contribution of HADHA to the effects of SPD on endothelial FAO and mitochondrial redox homeostasis. SPD treatment markedly attenuated pulmonary hypertension and vascular remodeling, accompanied by reduced inflammatory activation and endothelial injury. Metabolomic and lipidomic profiling indicated that SPD partially corrected pathological lipid-metabolic remodeling, including phosphatidylethanolamine-associated lipid alterations, and improved FAO-related mitochondrial function under lipotoxic stress. SPD reduced lipid accumulation and lipotoxic mitochondrial injury, inhibited PLIN2-vimentin-associated endothelial-to-mesenchymal transition (EndMT) marker changes, and increased PINK1/Parkin-related mitophagy markers together with TOM20/LC3B/LAMP2 colocalization, consistent with improved mitophagy-related mitochondrial quality control. Molecular dynamics simulation, cellular thermal shift assay, and microscale thermophoresis supported SPD-HADHA binding and SPD-associated HADHA stabilization. Importantly, HADHA knockdown markedly attenuated several effects of SPD on FAO-related function, mitochondrial redox balance, and lipotoxic phenotypes in PMVECs. These findings suggest that HADHA may contribute to the effects of SPD on fatty acid oxidation, redox homeostasis, and endothelial protection in PAH.
SN - 2213-2317
ER -