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Background <p>Myocardial ischemia/reperfusion (I/R) injury is a major cause of cardiac dysfunction, with ferroptosis playing a critical role. Transthyretin (TTR), a protein with neuroprotective and antioxidant properties, has been implicated in cardiovascular diseases. However, its specific role in myocardial I/R injury is unknown. This study explores the relationship between TTR and ferroptosis in myocardial I/R injury.</p> Methods and results <p>The mice myocardial I/R models were established, after which transcriptomic RNA sequencing was performed to identify key genes. H9c2 cardiomyocytes underwent hypoxia/reoxygenation (H/R) treatment accompanied by siRNA-mediated knockdown of TTR. Cells were divided into control (Con), H/R, si-NC + H/R, and si-TTR + H/R groups. Ferroptosis markers were analyzed, including Fe²⁺ (colorimetric assay), ROS (flow cytometry), GSH, and lipid peroxidation (LPO). The levels of TFR1, SLC7A11, GPX4, and ACSL4 was measured by qRT-PCR and Western blot. Mitochondrial morphology was assessed via transmission electron microscopy. The Con group maintained normal cell viability, redox balance, and mitochondrial morphology. The H/R group exhibited ferroptosis-associated damage, including increased ROS, Fe²⁺, LPO, and TFR1/ACSL4 expression, along with decreased GSH, SLC7A11, and GPX4. TTR knockdown (si-TTR + H/R) mitigated these effects, restoring cellular homeostasis and improving mitochondrial integrity.</p> Conclusions <p>TTR enhances ferroptosis during myocardial I/R injury. Its silencing protects cardiomyocytes by modulating iron metabolism, oxidative stress, and lipid peroxidation, making it a potential therapeutic target.</p>

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Knockdown of Transthyretin ameliorates ferroptosis in myocardial ischemia-reperfusion injury

  • 期刊论文

  • 发表日期：

    2026年4月28日

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  • Gege Liao,
  • Yuxin Li,
  • Jian Xu,
  • Zekun Lou,
  • Yang Liu,
  • Yanfeng Ma,
  • Dongye Li,
  • Feng Wang,
  • Tongda Xu

摘要

Background

Myocardial ischemia/reperfusion (I/R) injury is a major cause of cardiac dysfunction, with ferroptosis playing a critical role. Transthyretin (TTR), a protein with neuroprotective and antioxidant properties, has been implicated in cardiovascular diseases. However, its specific role in myocardial I/R injury is unknown. This study explores the relationship between TTR and ferroptosis in myocardial I/R injury.

Methods and results

The mice myocardial I/R models were established, after which transcriptomic RNA sequencing was performed to identify key genes. H9c2 cardiomyocytes underwent hypoxia/reoxygenation (H/R) treatment accompanied by siRNA-mediated knockdown of TTR. Cells were divided into control (Con), H/R, si-NC + H/R, and si-TTR + H/R groups. Ferroptosis markers were analyzed, including Fe²⁺ (colorimetric assay), ROS (flow cytometry), GSH, and lipid peroxidation (LPO). The levels of TFR1, SLC7A11, GPX4, and ACSL4 was measured by qRT-PCR and Western blot. Mitochondrial morphology was assessed via transmission electron microscopy. The Con group maintained normal cell viability, redox balance, and mitochondrial morphology. The H/R group exhibited ferroptosis-associated damage, including increased ROS, Fe²⁺, LPO, and TFR1/ACSL4 expression, along with decreased GSH, SLC7A11, and GPX4. TTR knockdown (si-TTR + H/R) mitigated these effects, restoring cellular homeostasis and improving mitochondrial integrity.

Conclusions

TTR enhances ferroptosis during myocardial I/R injury. Its silencing protects cardiomyocytes by modulating iron metabolism, oxidative stress, and lipid peroxidation, making it a potential therapeutic target.