Qili Qiangxin capsule alleviates doxorubicin-induced cardiotoxicity by inhibiting ferroptosis via lipid peroxidation

Background: Doxorubicin-induced cardiomyopathy (DIC) remains a major clinical challenge. Because it is driven by ferroptosis via lipid peroxidation in cardiomyocytes, targeting ferroptosis seems a promising therapeutic strategy, although developing effective cardioprotective agents has been challenging. Qili Qiangxin (QLQX) capsules, a clinically used traditional Chinese medicine for cardiovascular diseases, offer a potential approach for preventing and treating DIC. Methods: Cardiac tissues from a daunorubicin-treated acute myeloid leukemia patient were analyzed by single-nucleus RNA sequencing. A DIC model was established in tumor-bearing mice using intraperitoneal doxorubicin, followed by QLQX treatment. Cardiac function was evaluated by echocardiography, electrocardiography, and histopathology (hematoxylin and eosin and Masson’s trichrome staining). Serum biomarkers (creatine kinase, muscle brain isoenzyme, creatinine, aminotransferase) were measured biochemically. Multiomics analyses were performed, including fecal 16S ribosomal RNA sequencing along with a metabolomic, transcriptomic, and lipidomic profiling of cardiac tissues. Ferroptosis mechanisms were examined via western blot and immunohistochemistry for lipid peroxidation-related proteins. An antibiotic-depleted gut microbiota model was used to validate the role of the gut–heart axis in QLQX-mediated cardioprotection. Results: Single-nucleus RNA sequencing revealed enhanced mitochondrial dysfunction and lipid peroxidation in daunorubicin-exposed cardiomyocytes. QLQX improved survival (78% vs. 36%, P <0.01) and ejection fraction (EF; 67.3% vs. 57.5%, P <0.01) in doxorubicin (DOX)-treated mice, and reduced serum creatine kinase-MB (CK-MB; 740.9 vs. 407.5 U/L, P <0.01). QLQX lowered cardiac polyunsaturated fatty acids (PUFAs), upregulated glutathione peroxidase 4 (GPX4, 2‑fold) and ferroptosis suppressor protein 1 (FSP1, 2‑fold), and downregulated transferrin receptor (TFRC, 0.5‑fold). Antibiotic pretreatment reduced EF improvement by 69% and 4‑hydroxynonenal (4‑HNE) by 99% ( P <0.05). Conclusion: This study provides the multiomics evidence that QLQX alleviates DIC through a dual mechanism: (a) it suppresses cardiomyocyte ferroptosis by modulating the gut–heart axis and (b) inhibits lipid peroxidation. QLQX represents a first-in-class gut–heart axis modulator against chemotherapy-induced cardiotoxicity, bridging traditional medicine with precision cardioprotection.