Daucosterol ameliorates acute inflammation and fibrosis following myocardial infarction via regulation of the ZBTB16 protein

BACKGROUND AND PURPOSE: Myocardial infarction (MI) is accompanied by acute release of numerous inflammatory factors, leading to fibrosis and ultimately cardiac dysfunction. Daucosterol (DAU), a natural sterol compound, has been demonstrated to have anti-inflammatory properties and the ability to mitigate liver fibrosis. This study aims to investigate the therapeutic potential of DAU in MI and explores the underlying mechanisms. EXPERIMENTAL APPROACH: Various doses of DAU were administered to mice before MI. The cardioprotective effects of DAU were evaluated at both in vivo and in vitro levels. KEY RESULTS: In surgically-induced MI mouse models, DAU treatment reduced cardiac inflammation, attenuated myocardial fibrosis and improved cardiac function. Mechanistically, ZBTB16 expression was significantly suppressed in MI and reversed by DAU treatment by RNA-seq analysis and validation. Specifically, by restoring ZBTB16 protein levels, DAU inhibited S100A8 expression through transcriptional regulation of S100A8 by ZBTB16, thereby alleviating cardiac inflammation and fibrosis. Depletion of ZBTB16 exacerbated cardiac dysfunction in mice. CONCLUSION AND IMPLICATIONS: DAU alleviates post-infarction cardiac inflammation and fibrosis through modulation of ZBTB16/S100A8, thereby improving post-infarction cardiac remodelling and protecting heart function.