Metabolic-inflammatory memory: the common pathological basis and therapeutic targets of metabolic syndrome

Metabolic syndrome (MetS) is traditionally characterized by a cluster of abnormalities, including obesity, hyperglycemia, dyslipidemia, and hypertension, with clinical management historically centered on the stabilization of these individual parameters. However, the chronic, progressive nature of MetS and the persistent challenge of fully reversing its clinical manifestations indicate that its underlying pathophysiological mechanisms extend far beyond the mere summation of individual risk factors. Recent evidence reveals that the core pathogenesis of MetS involves a complex interplay between "metabolic memory" and "inflammatory memory." Metabolic memory represents the long-term imprint sustained at the cellular level from historical metabolic disturbances, mediated via epigenetic reprograming and mitochondrial dysfunction. Concurrently, inflammatory memory reflects the immune system's "trained immunity" (TI) under metabolic stress, which primes immune cells to maintain a persistent state of low-grade, chronic pro-inflammation. These two pathological processes interact closely through signaling cascades-such as nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), Janus kinase/signal transducer and activator of transcription (JAK-STAT), and Toll-like receptors (TLRs) pathways-thereby translating metabolic danger signals into chronic inflammation and the maladaptive regulation of lipid metabolism, insulin signaling, and vascular function. This cascade amplification mechanism, propagating from localized cellular memory to systemic inflammation, drives progressive end-organ damage in the heart, liver, kidneys, and vasculature, establishing the unifying pathological foundation of MetS and its associated complications. Consequently, clinical intervention strategies for MetS must transition from the superficial management of biochemical indicators toward therapies that specifically target and reverse this deeply ingrained metabolic-inflammatory memory. This review systematically constructs a comprehensive theoretical framework for metabolic-inflammatory memory in MetS and evaluates its clinical translational value, aiming to provide a mechanistic foundation for the development of targeted, curative clinical interventions.