A Berberine/rhein Co-Loaded Liposome Amplifies Antitumor Efficacy of Doxorubicin Via Metabolic Reprogramming

Objective Doxorubicin (DOX) remains a cornerstone chemotherapy for triple-negative breast cancer (TNBC), but its efficacy is limited by tumor resistance and aberrant lipid metabolism. This study investigates whether berberine and rhein—active components of the traditional Chinese medicine formula Dahuang Huanglian Xiexin Decoction—can enhance DOX efficacy in TNBC by modulating lipid metabolism. Methods This study developed a berberine and rhein liposomal formulation (BR-lipo) co-encapsulating berberine and rhein to improve their solubility and bioavailability. The combination of BR-lipo and DOX was evaluated in a 4 T1 mouse model of TNBC. Tumor growth and lung metastasis were monitored, while lipid metabolism alterations were assessed using Oil Red O staining, spatial metabolomics, and transcriptomic analysis. Results BR-lipo significantly enhanced the antitumor effect of DOX, suppressing both primary tumor growth and lung metastasis in 4 T1-bearing mice. Oil Red O staining revealed reduced lipid droplet accumulation in tumor tissues. Spatial metabolomics showed decreased monounsaturated fatty acids (MUFAs), potentially through inhibition of stearoyl-CoA desaturase 1 (SCD1). Transcriptomic analysis indicated downregulation of peroxisome proliferator-activated receptor γ (PPARγ), a key regulator of lipid metabolism. These findings were consistent across both in vivo and in vitro experiments. Conclusion Berberine and rhein delivered via liposomal formulation effectively modulate TNBC lipid metabolism, potentially through the PPARγ-SCD1 axis, and sensitize TNBC to DOX chemotherapy. This study provides a novel strategy to overcome DOX resistance in TNBC by targeting lipid metabolic pathways.