Hydroxysafflor Yellow A Attenuates Metabolic Dysfunction-associated Steatotic Liver Disease through Promoting Hepatocyte Survival and Reprogramming Macrophage Phenotype

Objective: To investigate the mechanisms underlying the amelioration of metabolic dysfunction-associated steatotic liver disease (MASLD) by hydroxysafflor yellow A (HYA). Materials and Methods: A mouse model of MASLD induced by administration of high-fat high-sugar water (HFSW)-, an oleic acid-palmitic acid (OAPA)-stimulated hepatocyte model, and a hepatocyte-macrophage coculture system were used. Transcriptomic analysis was used to elucidate the function and mechanisms of these models. Results: HYA significantly decreased lipid accumulation, restored fatty acid oxidation, and improved inflammatory responses, thereby alleviating hepatic steatosis in HFSW-fed mice. Furthermore, HYA promoted hepatocyte proliferation and suppressed apoptosis through activation of the viral oncogenic cellular-myelocytomatosis (c-Myc) signaling pathway. It concurrently polarized macrophages toward the M2 anti-inflammatory phenotype and enhanced their lysosomal phagocytic function to clear apoptotic hepatocytes. Conclusions: HYA exerts multifaceted anti-MASLD effects through the coordinated regulation of lipid metabolism and maintaining the balance between apoptosis and proliferation and immune microenvironment homeostasis; thus, HYA is a promising therapeutic candidate for clinical intervention.