Dendrophenol attenuates cardiac hypertrophy through inhibition of ferroptosis via the C-Jun/NCOA4 signaling pathway.

OBJECTIVES

Cardiac microvascular dysfunction contributes to the pathogenesis of cardiac hypertrophy (CH) and potentially progresses to cardiac failure. Dendrophenol (Den), a naturally derived compound isolated from Dendrobium moschatum, exhibits diverse biological properties, including anti-inflammatory, antioxidant, anti-angiogenic, anti-proliferative, and anti-metastatic effects. This investigation aimed to examine ferroptosis involvement in microvascular dysfunction and assess Den's capacity to suppress ferroptosis while ameliorating pressure overload-induced endothelial damage.

METHODS

A rat CH model was established, and comprehensive experimental approaches were implemented, including network pharmacology (NP), molecular docking, Western blot analysis, hematoxylin and eosin staining, wheat germ agglutinin staining, Masson staining, Gel-ink staining, immunohistochemistry, Laser speckle contrast analysis, immunofluorescence, quantitative reverse transcription polymerase chain reaction, and luciferase reporter gene.

KEY FINDINGS: NP methodologies were applied to predict Den's potential molecular targets. Echocardiographic assessments demonstrated that Den markedly enhanced cardiac function, while morphological staining analyses revealed that Den substantially suppressed CH development in rats. Additionally, Den ameliorated cardiac microvascular dysfunction in the abdominal aortic constriction-induced CH rat model. Mechanistic investigations revealed that Den suppresses C-Jun phosphorylation and decreases NCOA4 expression, consequently inhibiting ferroptosis in cardiac microvascular endothelial cells.

CONCLUSION

Den attenuated CH by suppressing ferroptosis in cardiac microvascular endothelial cells through the C-Jun/NCOA4 pathway.