Hypoxia-inducible factors link inflammation and lipid metabolism in atherosclerotic macrophages

Atherosclerosis is a chronic inflammatory disease driven by a complex interplay between immune cells, inflammation, metabolic dysfunction, and hypoxia. Among immune cells, macrophages interact bidirectionally with these factors, undergoing phenotypic and functional changes in response to the microenvironment, which contribute to both the progression and resolution of atherosclerosis. Recent studies have elucidated these dynamic interactions among these factors; however, research remains focused on individual aspects, and a more integrated understanding has yet to be fully established. Therefore, this review aimed to emphasize the importance of complex interactions among hypoxia, inflammation, and lipid metabolism, suggesting that the crosstalk among these response pathways operates actively and dynamically rather than following a simple cause-and-effect pathway. Further, this review highlights recent advances in understanding the inflammatory functions of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α in macrophages under hypoxic stress. In addition, we explore the systemic implications of HIF signaling in lipid-regulating organs such as the liver, intestine, and adipose tissue, emphasizing the emerging paradigm that HIF-2α acts as a metabolic switch coordinating lipid accumulation and inflammation. Finally, we summarize therapeutic approaches targeting HIFs, including HIF stabilizers and HIF-2α-selective antagonists. Collectively, this review offers a comprehensive multi-organ perspective on the immune-metabolic roles of HIFs in atherosclerosis, providing valuable insights into future therapeutic interventions.