TRPV1 Inhibits Ferroptosis and Mitophagy to Alleviate Heart Failure by Activating SFXN2

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.