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Huaban Tongmai Decoction ameliorates carotid artery atherosclerosis by inhibiting ferroptosis via the p53-Parkin mitophagy axis

ABSTRACT:

Background: Carotid artery atherosclerosis (CAS), has exhibited an increasing incidence in recent years. Although Huaban Tongmai decoction (HBTMD) shows considerable therapeutic potential against CAS, the specific molecular mechanisms of its action remain incompletely defined.

Purpose: This study aimed to explore and clarify the underlying mechanisms through which HBTMD mitigates CAS.

Methods: The components of HBTMD were analyzed using UHPLC-MS/MS. An ApoE-/- mouse model of CAS was established in vivo by combining a high-fat diet with carotid artery ligation. The extent of AS in carotid arteries was assessed using hematoxylin-eosin (HE) and Oil Red O (ORO) staining. Integrated proteomics and metabolomics analyses were conducted to screen key differentially expressed proteins (DEPs) and metabolites associated with HBTMD intervention. Potential targets and pathways were systematically explored. Transmission electron microscopy (TEM), quantitative real-time PCR (qRT-PCR), Western blot (WB), enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), and immunofluorescence (IF) were performed to evaluate markers related to ferroptosis and mitophagy, thus validating key pathway targets. In vitro, a cellular model of AS was established by inducing human umbilical vein endothelial cells (HUVECs) with ox-LDL. Ferroptosis and mitophagy levels were assessed using TEM, qRT-PCR, WB, ELISA, and reactive oxygen species (ROS) detection. Key pathway targets were further verified. Additionally, the ferroptosis inhibitor Ferrostatin-1 (Fer-1), the mitophagy inhibitor (Mdivi-1), and p53-specific small interfering RNA (siRNA) were employed to further clarify the mechanism of HBTMD.

Results: A comprehensive UHPLC-MS/MS analysis identified 684 chemical constituents within HBTMD. In vivo studies indicated significant reductions in both lipid accumulation and atherosclerotic plaque areas following HBTMD treatment. Integrated analyses involving proteomics and metabolomics suggested that the therapeutic efficacy of HBTMD might involve modulation of autophagy and ferroptosis pathways. Additional validations through in vitro and in vivo studies demonstrated that HBTMD administration effectively improved mitochondrial structural integrity, decreased the secretion of inflammatory cytokines, and inhibited ferroptosis. Furthermore, HBTMD decreased ROS levels and enhanced mitophagy activity, an effect partially reversed by the mitochondrial division inhibitor Mdivi-1.In vitro, knockdown of the p53 gene did not further enhance the regulatory effects of HBTMD on ferroptosis- and mitophagy-related proteins.

Conclusion: This study provides the first evidence that the anti-atherosclerotic effect of HBTMD occurs via the regulation of the p53-Parkin signaling pathway, thereby enhancing mitophagy and suppressing ferroptosis.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS13908 | MetaboLights | 2026-02-15

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13908_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS13908_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13908_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13908_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Edaravone dexborneol (EDB) is widely recognized for its anti-inflammatory and antioxidant properties and is clinically applied in the treatment of acute cerebral infarction. Ferroptosis is a critical process in the pathophysiology of brain injury following intracerebral hemorrhage (ICH). However, it remains unclear whether EDB can ameliorate ICH through the modulation of ferroptosis. This study aimed to evaluate the function and mechanism of EDB in treatment of ICH. With a rat ICH model, animal behavior tests, histopathological staining, magnetic resonance imaging and evans blue staining were used to evaluate the neural protective function of EDB on ICH rats. The potential molecular mechanism was investigated using RNA sequencing. With the administration of Fer-1, a range of ferroptosis-related biomarkers, including Fe2+, 4-hydroxynonenal, malondialdehyde, etc., were analyzed to to ascertain whether EDB confers neuroprotective effects through the modulation of P53/GPX4 pathways to inhibit ferroptosis. Finally, the findings were further corroborated using an in vitro ICH model with a P53 inhibitor. EDB has the potential to markedly enhance nerve and motor function, mitigate pathological damage, facilitate hematoma clearance, and repair BBB injury in ICH rats. KEGG analysis revealed that the differentially expressed genes were associated with signaling pathways, including P53 and ferroptosis. Both EDB and Fer-1 substantially reduced the concentrations of Fe2+, 4-hydroxynonenal, malondialdehyde, increased the amount of anti-oxidants, decreased the expression of P53, and concurrently upregulated the expression of GPX4. Besides, the P53 inhibitor PFT-α was observed to significantly reduce the levels of 4-HNE and lipid peroxides, while concurrently increasing the expression of GPX4. This investigation has shed light on the crucial neuroprotective role of EDB by regulating ferroptosis in ICH disease, which provided a theoretical basis for the clinical application of EDB in the treatment of ICH.

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Huaban Tongmai Decoction ameliorates carotid artery atherosclerosis by inhibiting ferroptosis via the p53-Parkin mitophagy axis

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