Related Experiment Video
Updated: Sep 17, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
TRPV1 Inhibits Ferroptosis and Mitophagy to Alleviate Heart Failure by Activating SFXN2
Pan Liu1, Shiguang Wang2, Liya Li1
1Graduate School, Anhui University of Chinese Medicine, Special Project of Xin'an Medical and Traditional Chinese Medicine Modernization Research Institute of Great Health Research Institute, 230012 Hefei, Anhui, China.
Insights
Transient receptor potential cation channel subfamily V member 1 (TRPV1) overexpression protects against heart failure by regulating mitochondrial autophagy and ferroptosis via the SFXN2 pathway. This highlights TRPV1 as a potential therapeutic target for heart failure.
Area of Science:
- Cardiovascular Research
- Mitochondrial Biology
- Cellular Physiology
Background:
- Heart failure (HF) is a major global health issue.
- Transient receptor potential cation channel subfamily V member 1 (TRPV1) is implicated in cardiac function, but its role in HF is unclear.
- Investigating TRPV1's role in mitochondrial autophagy in HF is crucial.
Purpose of the Study:
- To determine the regulatory role of TRPV1 in mitochondrial autophagy in heart failure.
- To elucidate the molecular mechanisms underlying TRPV1's effects in HF.
- To identify potential therapeutic targets for HF.
Main Methods:
- AC16 cardiomyocytes were treated with angiotensin II (Ang II) to induce oxidative stress.
- A pressure overload-induced HF mouse model was created using transverse aortic constriction (TAC).
- Cardiac-specific TRPV1 overexpression was achieved using Adeno-associated virus 9 (AAV9), followed by RNA sequencing, bioinformatics analysis, and assessment of mitophagy and ferroptosis markers.
Main Results:
- TRPV1 overexpression reduced Ang II-induced cardiomyocyte death, intracellular calcium, and oxidative stress.
- TRPV1 was found to correlate with sideroflexin 2 (SFXN2) in mitochondrial genes.
- In the TAC model, TRPV1 overexpression improved cardiac function and suppressed mitophagy markers by activating SFXN2, enhancing antioxidant capacity (GPX4, GSH, SOD) and reducing oxidative damage (MDA, Fe2+).
Conclusions:
- TRPV1 overexpression alleviates Ang II-induced myocardial injury in heart failure.
- The protective effects are mediated by the TRPV1-SFXN2 axis, which suppresses mitophagy and ferroptosis.
- TRPV1 represents a promising therapeutic target for heart failure.
Background:
Heart failure (HF) continues to represent a significant global public health concern. Transient receptor potential cation channel subfamily V member 1 (TRPV1) is a calcium-permeable channel that has been linked to cardiac disease and function. However, its significance in HF and underlying processes is unknown. This study aims to determine the regulatory role of TRPV1 in mitochondrial autophagy in HF.
Methods:
AC16 cardiomyocytes were exposed to angiotensin II (Ang II) to simulate pathological conditions, and changes in oxidative stress were assessed. Transverse aortic constriction (TAC) was used to create a pressure overload-induced HF mouse model, and cardiac-specific TRPV1 overexpression was achieved by Adeno-associated virus 9 (AAV9). RNA sequencing and bioinformatics analysis were performed to identify TRPV1-related mitochondrial genes. Finally, the effects of TRPV1 overexpression and sideroflexin 2 (SFXN2) knockdown on markers related to mitophagy and ferroptosis were analyzed.
Results:
In vitro, TRPV1 overexpression drastically decreased intracellular Ca2+ levels, lessened oxidative stress, and reduced Ang II-induced cell death (p < 0.05). Bioinformatics analysis identified seven mitochondrial genes associated with TRPV1, among which SFXN2 showed a strong correlation with TRPV1 (p < 0.05). Overexpressing cardiac-specific TRPV1 in the TAC model led to improved cardiac function, higher fractional shortening and ejection fraction, and reduced levels of mitophagy markers (p < 0.05). Mechanistically, TRPV1 activated SFXN2, increasing glutathione peroxidase 4 (GPX4) expression and antioxidant capacity (glutathione (GSH), superoxide dismutase (SOD)) while decreasing malondialdehyde (MDA) and ferrous iron (Fe2+) levels (p < 0.05). These protective effects were removed by SFXN2 knockdown. Furthermore, the TRPV1-SFXN2 axis suppressed mitophagy by modulating the PTEN-induced kinase 1 (PINK1)-Parkin-sequestosome 1 (SQSTM1) axis.
Conclusion:
Our results show that TRPV1 overexpression alleviates Ang II-induced myocardial injury in HF. This protective effect is mediated through SFXN2-dependent mitophagy and ferroptosis, highlighting TRPV1 as a potential therapeutic target for HF.
Related Concept Videos
01:29Heart Failure II: Pathophysiology
01:17Pathophysiology of Heart Failure
01:30Heart Failure V: Medical Management
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System
01:16Necrosis
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
01:22Heart Failure VI: Adjunct Therapies