Luhong formula inhibits ferroptosis via the SLC7A11/GPX4 axis to protect against myocardial ischemia/reperfusion injury

Luhong Formula ( LHF) is a traditional Chinese herbal formula historically used to support heart function and improve circulation. This study provides scientific evidence for its cardioprotective role against myocardial ischemia/reperfusion injury through the inhibition of ferroptosis. Ferroptosis, a form of regulated cell death characterized by iron accumulation and lipid peroxidation, plays a critical role in myocardial ischemia/reperfusion (I/R) injury. However, effective strategies to attenuate ferroptosis-induced cardiac damage remain limited. This study aimed to explore the cardioprotective effects of LHF and its underlying mechanisms in suppressing ferroptosis. In vivo, I/R was developed by ligating and then releasing the left anterior descending artery. Heart tissue and blood were collected 24 h post-reperfusion to evaluate cardiac injury and ferroptosis. In vitro, neonatal rat cardiomyocytes were isolated to create a hypoxia/reoxygenation model. By overexpressing and/or silencing SLC7A11 in cardiomyocytes, we assessed the impact of LHF intervention on cellular damage, ferroptosis, and SLC7A11 degradation. LHF significantly improved cardiac function, reduced infarct size, and attenuated oxidative stress and ferroptosis both in vivo and in vitro. Mechanistically, LHF upregulated the expression of SLC7A11 and GPX4, restored antioxidant capacity, and reduced Fe 2+ overload and lipid peroxidation. Overexpression of SLC7A11 mimicked the protective effects of LHF, while SLC7A11 knockdown abolished them. Notably, LHF reduced the ubiquitination of SLC7A11, suggesting that it enhances SLC7A11 stability and function under stress conditions. LHF protects against myocardial I/R injury by inhibiting ferroptosis through activation of the SLC7A11/GPX4 axis. These findings highlight SLC7A11 as a potential therapeutic target and provide novel insights into the anti-ferroptotic mechanisms of traditional Chinese medicine.