Study on the mechanism of Huangqi Chifeng decoction regulating ferroptosis inhibiting smooth muscle cells derived foam cell formation.

ETHNOPHARMACOLOGICAL RELEVANCE

Chinese medicine, specifically Huangqi Chifeng Decoction (HQCF), is recognized for its efficacy in treating atherosclerosis (AS), a common cardiovascular disease. Despite its established benefits in addressing Qi deficiency, blood stasis, and collateral obstruction, the precise mechanism through which HQCF affects AS remains unclear.

AIM OF THE STUDY

This study investigated the potential of HQCF to mitigate AS by suppressing smooth muscle cell (SMC) foam formation through the ferroptosis pathway.

MATERIALS AND METHODS

An AS model was established using ApoE mice fed a high-fat diet (HFD), and the role of HQCF in regulating ferroptosis in AS was examined. Using a single-cell proteomics analysis strategy, we identified the primary targets of HQCF in SMCs. Additionally, an oxidized low-density lipoprotein (ox-LDL)-treated SMC-derived foam cell model was established. The effects HQCF on SMC ferroptosis were analyzed, and ox-LDL-induced SMCs were pretreated with small interfering RNA (siRNA) and overexpressing carrier plasmids (pcDNA) to identify potential therapeutic targets, for specifically thioredoxin (TXN).

RESULTS

HQCF the pathological state of the aorta in ApoE mice, regulated lipid levels, improved antioxidant capacity, modulated the phenotypic transformation of SMCs, and maintained the dynamic balance of extracellular matrix degradation and remodeling. Additionally, HQCF may inhibit ferroptosis via positive regulation of the GPX4/xCT signaling pathway. Single-cell proteomics revealed 36 common differentially expressed proteins (DEPs), suggesting that HQCF's treatment of AS may be associated with the regulation of cellular function and redox homeostasis. The abnormal expression of TXN in SMCs may be related to the phenotypic transition induced by AS. HQCF was also found to ameliorate oxidative stress and mitochondrial dysfunction during SMC foaming. Moreover, ferroptosis was involved in ox-LDL-induced foam cell formation, and HQCF alleviated these pathologies by inhibiting ferroptosis. The protective effect of HQCF on SMCs was enhanced by TXN overexpression but partially reversed by TXN knockdown, further indicating that HQCF's regulation of SMC function and inhibition of ferroptosis is, at least in part, mediated by TXN.

CONCLUSION

These findings suggest that HQCF protects SMCs from ferroptosis by regulating the TXN/xCT/GPX4 pathway, ameliorating the aortic pathological state, alleviating oxidative stress, and maintaining mitochondrial homeostasis in mice.