Immunometabolic regulation of macrophage function in cardio–hepatic–renal comorbidities: Mechanisms and therapeutic opportunities

This review examines metabolic comorbidities affecting the heart, liver and kidney. The clinical prevalence of cardiohepatorenal metabolic comorbidities associated with obesity and type 2 diabetes is substantial. Chronic low-grade inflammation serves as the fundamental pathogenic mechanism. Abnormal macrophage activation is associated with metabolic disorders and damage to multiple organs. The conventional M1/M2 binary classification fails to adequately capture the heterogeneity of macrophages in vivo. Previous studies have primarily focused on the investigation of individual organs, leaving the cross-organ immune-metabolic linkage mechanism poorly understood. Furthermore, targeted interventions often lack precision. In this study, we systematically summarize the roles of macrophage polarization, phenotypic remodeling and metabolic activation in the injury of three metabolic organs. We also analyze their mediating functions in inter-organ immune-metabolic crosstalk and the associated pathological connections. Glycolipid toxicity impairs the glycolipid metabolism of macrophages via the NLRP3/SIRT pathway, resulting in a pro-inflammatory polarization advantage. Specific subsets of macrophages, including CCR2+,TREM2+,and CD206+CD68+,are involved in mediating myocardial remodeling, liver fibrosis, and renal interstitial injury, respectively.Medications such as SGLT2 inhibitors and GLP-1 receptor agonists may provide multi-organ protection by modulating macrophage activity. The current research presents several limitations, including species differences between humans and mice, ambiguous temporal transformation rules of macrophages, and inadequate specificity of targeted preparations.Future efforts should leverage spatial multi-omics and gene editing technologies to analyze the global regulatory network and develop highly selective targeted strategies. This approach can offer theoretical support for the integrated and precise prevention and management of metabolic comorbidities.