BAOXIN granules reverse ferroptosis through the solute carrier family 7 member -glutathione-glutathione peroxidase 4 axis in ischemia-induced heart failure in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Ferroptosis is a newly recognized form of non-apoptotic cell death characterized by significant iron accumulation and lipid peroxidation. The suppression of cardiomyocyte ferroptosis represents a promising therapeutic approach for heart failure (HF). BAOXIN granules (BXC), a traditional Chinese medicine approved by the China Food and Drug Administration, are widely used for the treatment of HF. This formulation is traditionally used to nourish qi and yin, promote blood circulation, and unlock meridians. However, the molecular mechanism underlying the efficacy of BXC in treating ischemia-induced HF remains unclear.

AIM OF THE STUDY: To evaluate the therapeutic effects of BXC on HF and elucidate its role in the inhibition of cardiomyocyte ferroptosis.

MATERIALS AND

METHODS

The chemical ingredients of BXC and its serum composition were identified using liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (LC-QTOF-MS). A rat model of ischemia-induced HF was established by ligating the left anterior descending coronary artery. Cardiac function and structural damage were assessed using echocardiography, hematoxylin-eosin (H&E) staining, Masson staining, and enzyme-linked immunosorbent assay (ELISA). Proteomic analysis was employed to explore the possible mechanisms of BXC. Mitochondrial dysfunction was evaluated by measuring the levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP). The inhibition of ferroptosis was assessed by measuring the levels of malondialdehyde (MDA), the activity of superoxide dismutase (SOD), and the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), prostaglandin-endoperoxide synthase 2 (PTGS2), and ferritin light chain (FTL). Potential targets, including the solute carrier family 7 member 11 (SLC7A11)-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis, were also investigated.

RESULTS

BXC significantly improved cardiac function and reduced myocardial fibrosis in rats. Proteomic analysis revealed that BXC modulates energy metabolism and inhibits cardiomyocyte ferroptosis. BXC enhanced mitochondrial energy metabolism, as evidenced by decreased ADP/ATP and AMP/ATP ratios. It also reversed ferroptosis by restoring MDA levels and SOD activity, normalizing ACSL4, PTGS2, and FTL expression. Furthermore, BXC reactivated the SLC7A11-GSH-GPX4 axis, thereby suppressing ferroptosis. Analysis of the serum composition following BXC administration identified 10 ingredients that interact with the SLC7A11-GSH-GPX4 axis.

CONCLUSION

This study provides evidence for the efficacy of BXC in treating HF following myocardial infarction. BXC exerts cardioprotective effects by inhibiting ferroptosis via modulation of the SLC7A11-GSH-GPX4 axis.