As a natural flavonoid, the flavonoid luteolin is characterized by its powerful antioxidant and anti-inflammatory effects. While its precise mechanisms require further elucidation, existing evidence confirms its efficacy in ameliorating myocardial ischemia–reperfusion injury (MIRI). This research was designed to investigate the mechanism through which luteolin protects against MIRI. We established MIRI rat models through the ligation of left anterior descending coronary artery (LAD). To evaluate the cardioprotective effects of luteolin, echocardiographic analysis was performed, Hematoxylin and Eosin (HE) staining, and serum cardiac injury markers creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH). Cardiac vascular permeability was determined using Evans blue staining. To mimic ischemia–reperfusion injury, endothelial cells (ECs) were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro. Endothelial cell barrier function was evaluated through F-actin phalloidin staining and FITC-Dextran fluorescence leakage experiments. To elucidate the molecular mechanism, FOXP1 small interfering RNA (siRNA) and NLRP3 inhibitor MCC950 were administered. In MIRI rats, luteolin significantly improved cardiac function and preserved endothelial barrier integrity. These effects were associated with upregulation of FOXP1 and suppression of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. In OGD/R-treated endothelial cells, luteolin restored barrier function and cell viability. The protective effects of luteolin were abolished after FOXP1 silencing. Pharmacological NLRP3 inhibition (MCC950) mirrored luteolin’s protection. Our study indicates that luteolin enhances endothelial barrier function and attenuates MIRI via the FOXP1-NLRP3 pathway. The current study provides a potential drug for MIRI treatment.

Doxorubicin (DOX) remains a cornerstone of chemotherapy but is limited by dose-dependent doxorubicin-induced cardiotoxicity (DIC). Recent evidence suggests that mitochondrial dysfunction, particularly oxidative stress and ferroptosis, drives DIC progression. While the flavonoid Calycosin (CAL) is known for its cardioprotective properties, the precise mechanism by which it maintains mitochondrial homeostasis remains elusive. This study aimed to investigate the effects of CAL against DIC and to explore the mechanisms by which CAL regulates mitochondrial integrity and iron homeostasis. Using both in vitro H9c2 cardiomyocytes and in vivo C57BL/6 mice, we demonstrate that CAL significantly restores cardiac contractility and reduces myocardial damage. Transcriptomic analysis indicated that CAL protected mitochondrial function and inhibited ferroptosis. Transmission Electron Microscopy (TEM) showed that CAL preserved mitochondrial structure. Assessments of the lipid peroxidation marker malondialdehyde (MDA) and superoxide dismutase (SOD) confirmed that CAL alleviated oxidative stress, while 8-OHdG staining verified its restoration of mitochondrial DNA integrity. Molecular docking identified the affinity of CAL with NRF2 and NRF1. CAL activated the NRF2/NRF1-TFAM axis both in vivo and in vitro, promoting mitochondrial biogenesis and respiratory function, while regulating iron homeostasis via FTMT and FPN. Knockdown or inhibition of NRF2/NRF1 abolished these protective effects of CAL. Our findings suggest that CAL acts as a dual-regulator of mitochondrial transcriptional machinery and iron metabolism, offering a novel therapeutic strategy to safeguard mitochondria against ferroptosis.