Galnt4 Knockdown Modulates Lysosomal Function to Reduce Foam Cell Formation and Attenuate Atherosclerotic Plaque Progression

ABSTRACT Atherosclerosis, a chronic lipid metabolism disorder, remains a leading cause of morbidity and mortality. While Galnt4, an O‐glycosyltransferase, has been implicated in several diseases, its role in atherosclerosis remains poorly understood. This study aimed to elucidate the effects of Galnt4 dysregulation on atherosclerotic lesion formation and its involvement in macrophage lipid metabolism. In this study, we analyzed Galnt4 expression in atherosclerotic plaque tissues and foam cells. In vivo and in vitro experiments were conducted to assess the effects of Galnt4 deficiency on macrophage foam cell formation and plaque development. O‐glycoproteomic analysis was performed to explore the mechanistic role of Galnt4 in foam cell formation. Our results revealed that Galnt4 expression was significantly elevated in plaque tissues and foam cells, predominantly localized in macrophages. Galnt4 knockdown reduced macrophage foam cell formation and attenuated plaque development. Mechanistic studies reflected that Galnt4 regulates foam cell formation by modulating lysosomal function, specifically through Lamp‐1 glycosylation, leading to decreased lysosomal free cholesterol and reduced foam cell formation. In conclusion, our findings highlighted that Galnt4 in macrophages plays a crucial role in modulating Lamp‐1 glycosylation and lysosomal function, thereby impacting foam cell formation and atherosclerosis progression. These findings identify Galnt4 as a potential therapeutic target for atherosclerosis.