Monocytes and macrophages are critically involved in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). Accumulating evidence indicates that monocytes and macrophages can develop innate immune memory and exhibit sustained pro-inflammatory properties in response to stimuli such as hyperlipidemia and hyperglycemia. Persistent activation of innate immune cells is referred to as trained immunity (TI), a process mediated by metabolic and epigenetic reprogramming. This concept provides insight into why cardiovascular events remain challenging to reduce significantly, even when key risk factors for atherosclerosis (AS) are effectively controlled. Previous studies have shown that both pathogen-associated molecular patterns (PAMPs) or endogenous damage-associated molecular patterns (DAMPs) can activate TI in monocytes/macrophages through various receptors, such as Dectin-1, cluster of differentiation 36 (CD36), and glucose transporter 1 (GLUT1), thereby inducing metabolic reprogramming and epigenetic modifications (e.g., histone lactylation and methylation). Moreover, recent research has increasingly focused on developing preventive and therapeutic strategies for ASCVD by modulating TI. In this review, we systematically elucidate the regulatory mechanisms underlying the induction of TI in monocytes and macrophages, and analyze the impact of TI on the persistence of chronic inflammatory states, which may ultimately contribute to the development of ASCVD. We summarize key signaling pathways associated with TI, as well as the metabolic and epigenetic reprogramming processes involved, covering the activation mechanisms of ASCVD-related risk factors, alterations in metabolic regulation, and representative epigenetic modification markers. Finally, we discuss current immunotherapeutic strategies for ASCVD based on the mechanisms of TI and highlight their progress in research.
Zhang et al. (2026) studied this question.