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Background <p>Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation and oxidative membrane damage. Increasing evidence suggests that ferroptosis contributes to the pathogenesis of cardiovascular diseases; however, its role in pressure overload-induced cardiac hypertrophy (PO-CH) remains incompletely understood. α-Synuclein (SNCA), a protein widely studied in neurodegenerative diseases, has been implicated in the regulation of iron metabolism and oxidative stress, suggesting a potential link between SNCA and ferroptosis in cardiac remodeling.</p> Methods <p>Transcriptomic data from the GSE36961 dataset were integrated with ferroptosis-related genes obtained from the FerrDb database to identify candidate regulators involved in PO-CH. Differentially expressed genes were screened and subjected to functional enrichment analysis to identify hub genes. Experimental validation was performed using a transverse aortic constriction (TAC) mouse model, human hypertrophic myocardial specimens, and an angiotensin II–induced H9C2 cardiomyocyte hypertrophy model. Cardiac structural and metabolic remodeling were evaluated by echocardiography and ^18F-FDG PET-CT imaging. Gene and protein expression levels were determined using qRT-PCR, Western blotting, and histological analyses. Ferroptosis modulation was further investigated using the inhibitor ferrostatin-1 (Fer-1) and the inducer erastin. Lipid peroxidation was assessed by measuring 4-HNE and MDA levels via ELISA and by BODIPY 581/591 C11 staining.</p> Results <p>Bioinformatic analyses identified six ferroptosis-associated differentially expressed genes in PO-CH, including SNCA, CDKN1A, PDK4, STAT3, TIMP1, and ZFP36. Among these genes, SNCA was significantly upregulated and selected as the hub gene for further investigation. In TAC-induced hypertrophic mice and human hypertrophic myocardial tissues, SNCA expression was markedly increased, whereas the ferroptosis regulator GPX4 was significantly decreased. PET-CT imaging revealed increased myocardial glucose uptake, indicating metabolic remodeling during cardiac hypertrophy. In vitro experiments demonstrated that inhibition of ferroptosis by Fer-1 reduced SNCA protein expression, whereas induction of ferroptosis by erastin further increased SNCA levels. Moreover, Fer-1 significantly reduced 4-HNE, MDA, and BODIPY green/red ratio, while erastin increased these lipid peroxidation markers.</p> Conclusions <p>These findings identify SNCA as a novel ferroptosis-associated gene involved in PO-CH. Our results highlight a potential mechanistic link between ferroptosis, metabolic remodeling, and myocardial hypertrophy, suggesting that SNCA may serve as a potential biomarker or a candidate for further mechanistic studies for pathological cardiac remodeling.</p>

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SNCA is associated with ferroptosis-related cardiomyocyte injury in pressure overload-induced cardiac hypertrophy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月17日

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  • Fei Xiao,
  • Huili Li,
  • Chengbin wang,
  • Huimin Wu,
  • Jiarui Wang,
  • Shuwen Li,
  • Gang Li,
  • Yongmei Wang,
  • Sheng Wang

摘要

Background

Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation and oxidative membrane damage. Increasing evidence suggests that ferroptosis contributes to the pathogenesis of cardiovascular diseases; however, its role in pressure overload-induced cardiac hypertrophy (PO-CH) remains incompletely understood. α-Synuclein (SNCA), a protein widely studied in neurodegenerative diseases, has been implicated in the regulation of iron metabolism and oxidative stress, suggesting a potential link between SNCA and ferroptosis in cardiac remodeling.

Methods

Transcriptomic data from the GSE36961 dataset were integrated with ferroptosis-related genes obtained from the FerrDb database to identify candidate regulators involved in PO-CH. Differentially expressed genes were screened and subjected to functional enrichment analysis to identify hub genes. Experimental validation was performed using a transverse aortic constriction (TAC) mouse model, human hypertrophic myocardial specimens, and an angiotensin II–induced H9C2 cardiomyocyte hypertrophy model. Cardiac structural and metabolic remodeling were evaluated by echocardiography and ^18F-FDG PET-CT imaging. Gene and protein expression levels were determined using qRT-PCR, Western blotting, and histological analyses. Ferroptosis modulation was further investigated using the inhibitor ferrostatin-1 (Fer-1) and the inducer erastin. Lipid peroxidation was assessed by measuring 4-HNE and MDA levels via ELISA and by BODIPY 581/591 C11 staining.

Results

Bioinformatic analyses identified six ferroptosis-associated differentially expressed genes in PO-CH, including SNCA, CDKN1A, PDK4, STAT3, TIMP1, and ZFP36. Among these genes, SNCA was significantly upregulated and selected as the hub gene for further investigation. In TAC-induced hypertrophic mice and human hypertrophic myocardial tissues, SNCA expression was markedly increased, whereas the ferroptosis regulator GPX4 was significantly decreased. PET-CT imaging revealed increased myocardial glucose uptake, indicating metabolic remodeling during cardiac hypertrophy. In vitro experiments demonstrated that inhibition of ferroptosis by Fer-1 reduced SNCA protein expression, whereas induction of ferroptosis by erastin further increased SNCA levels. Moreover, Fer-1 significantly reduced 4-HNE, MDA, and BODIPY green/red ratio, while erastin increased these lipid peroxidation markers.

Conclusions

These findings identify SNCA as a novel ferroptosis-associated gene involved in PO-CH. Our results highlight a potential mechanistic link between ferroptosis, metabolic remodeling, and myocardial hypertrophy, suggesting that SNCA may serve as a potential biomarker or a candidate for further mechanistic studies for pathological cardiac remodeling.