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High-salt diet in macrophage-associated metabolic disorders: Mechanisms and therapeutic implications
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DOI：10.1097/CM9.0000000000004098.png)
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Abstract
En 中文
High-salt diet (HSD) has emerged as a prevalent environmental factor that exacerbates chronic inflammation and insulin resistance in obesity-associated type 2 diabetes (T2D) by modulating macrophage polarization, metabolic reprogramming, and epigenetic imprinting. Current evidence demonstrates that HSD activates p38/mitogen-activated protein kinase (MAPK), nuclear factor kappa-B (NF-κB), and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling pathways, by which it drives macrophage polarization toward a proinflammatory M1 phenotype while inducing a glycolysis-dominant metabolic shift, thereby establishing a persistent “metabolic memory”. Moreover, HSD orchestrates metabolic memory in macrophages through coordinated epigenetic machinery, including histone modifications (Trimethylation of histone H3 at lysine 4 [H3K4me3] and Acetylation of histone H3 at lysine 27 [H3K27ac]), DNA methylation, and noncoding RNAs (e.g., long non-coding RNA MALAT1 and miR-155), leading to sustained inflammatory phenotypes. In multiple metabolic organs (e.g., adipose tissue, liver, pancreas, and gut), the HSD–macrophage axis aggravates systemic insulin resistance through shared proinflammatory signaling and other tissue-specific mechanisms. Most importantly, therapeutic strategies targeting the NLRP3 inflammasome, metabolic pathways, and epigenetic alterations offer novel approaches for managing metabolic inflammation. Future investigations are encouraged to leverage lineage tracing, single-cell sequencing, and spatial multi-omics technologies to advance the development of precision medicine for macrophage-associated metabolic disorders.
Keywords:
High-salt diet
Macrophages
Metabolic memory
Epigenetic alteration
Metabolic disorders
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