Roles of inflammation and metabolic dysfunction in cardiovascular diseases: molecular mechanisms and therapeutic targets

Fig. 1. Overall interpretive framework of metabolism–inflammation crosstalk in cardiovascular disease. IRI, pressure overload and metabolic overload/lipotoxic stress converge on shared cellular stress responses, including mitochondrial stress, redox imbalance, DAMP release and inflammatory priming. The left panel outlines the staged inflammatory response described in Sect. "Core cardiovascular inflammatory pathways: from danger-signal sensing to chronic remodeling". DAMPs released from stressed cardiomyocytes activate PRRs/TLR4-dependent NF-κB priming in macrophages, thereby licensing NLRP3–ASC–caspase-1 inflammasome activation and downstream IL-1β, IL-6 and TNF-α amplification. Endothelial activation, VCAM-1/ICAM-1 expression and chemokine gradients organize leukocyte recruitment, after which efferocytosis and tissue repair compete with persistent inflammation and fibrotic remodeling. The right panel summarizes the metabolic routing required to interpret this inflammatory sequence. Glucose enters glycolysis through HK-, PFK-1- and PK-regulated steps to generate pyruvate, which can be reduced to lactate or converted to acetyl-CoA for TCA-cycle entry; G-6-P can also be diverted into the…

Fig. 2. Cell–cell topology of metabolic-inflammatory crosstalk in cardiovascular disease. This figure maps spatial communication routes through which metabolic programs acquire inflammatory, reparative or remodeling-associated meaning in cardiovascular disease. a At the vascular/plaque interface, endothelial glycolytic activation, adhesion and chemokine cues, plaque macrophage hypoxia and S1P-favored ceramide/S1P rewiring shape leukocyte recruitment, macrophage-rich inflammation and plaque stability. b In the myocardium/remodeling compartment, stressed cardiomyocytes provide mitochondrial, redox and amino-acid stress cues that converge on macrophage NLRP3 activation, while macrophage TCA remodeling separates succinate–HIF-1α–IL-1β inflammatory output from itaconate–NRF2 restraint. This compartment also links macrophage-derived profibrotic signaling to fibroblast glycolysis, TGF-β–Smad activation, ECM deposition and FAO/OXPHOS-supported efferocytosis during resolution. c T-cell metabolic bias in plaque immunity is shown as a context-dependent balance between glycolysis/fatty acid synthesis-associated Th17 programs and oxidative metabolism-associated Treg programs. d In HFpEF, lymphatic…

Fig. 3. Stage-dependent interpretation of metabolic-inflammatory programs across cardiovascular injury and remodeling. This figure illustrates how timing and cellular source determine the interpretation of metabolic-inflammatory programs during cardiovascular injury and remodeling. During acute metabolic adaptation, early ischemia–reperfusion or acute metabolic stress can engage cardiomyocyte-protective glucose programs, including HSPA12A-associated glycolysis and histone H3 lactylation, acute glycolytic support, and PPP/G6PD-dependent NADPH–GSH redox buffering. These programs are linked to adaptive outcomes such as survival and ROS limitation. During inflammatory amplification, damaged mitochondria, mtROS, mtDNA and tissue-stress cues promote macrophage activation and NLRP3-related signaling, while succinate- and PKM2-associated HIF-1α–IL-1β signaling and FAO mismatch/acylcarnitine accumulation may facilitate inflammasome activation under primed conditions, cytokine amplification and mitochondrial stress. During resolution/repair, efferocytosis, FAO/OXPHOS-supported phagocyte function and itaconate–NRF2 restraint shift the response toward inflammatory resolution and tissue repair.…

Fig. 4. Disease-prioritized integrative model of metabolic-inflammatory crosstalk in cardiovascular disease. The figure organizes metabolic-inflammatory mechanisms according to disease phenotype, dominant cellular compartment, priority metabolic module and disease output. Green modules denote adaptive, reparative or stabilizing programs; red modules denote inflammatory, injury-promoting or profibrotic programs; and yellow modules denote phenotype-dependent or incompletely resolved mechanisms whose interpretation requires additional information on cell compartment, flux direction or disease setting. Solid arrows indicate assigned mechanistic links within the depicted disease context, dashed arrows indicate conditional or unresolved links that should not yet be interpreted as fixed causal routes. a In myocardial infarction/ischemia–reperfusion injury, acute glucose adaptation in cardiomyocytes is positioned as a survival module shaped by PPP/G6PD-dependent NADPH–GSH buffering and HSPA12A–H3K56la signaling, whereas FAO mismatch, acylcarnitine accumulation and mtROS/mtDNA/NLRP3 activation shift the same injury context toward inflammatory damage. Timing determines whether this biology is…