TAK1 Is Associated with Lipid-Induced Macrophage Polarization in Obesity Cardiomyopathy: Evidence from Network Pharmacology and Experimental Validation

Objective: To investigate whether TAK1 regulates lipid-induced macrophage polarization and contributes to inflammatory progression in obesity cardiomyopathy (OCM). Background: OCM is characterized by lipid overload, chronic low-grade inflammation, macrophage polarization imbalance, and myocardial remodeling. Preliminary internal RNA-Seq data suggested that TAK1 may be involved in obesity-related cardiac pathological remodeling. However, its regulatory role in lipid-induced macrophage polarization remains unclear. Methods: Network pharmacology was performed to determine whether TAK1 was located within an OCM-related metabolic-inflammatory target network. OCM-related targets and compound-intervention-related targets were retrieved from public databases, followed by overlap analysis, protein–protein interaction analysis, and GO/KEGG enrichment. A high-fat diet-induced rat model was used to assess cardiac function, myocardial remodeling, TAK1 expression, and cardiac macrophage polarization. In vitro, NR8383 macrophages were exposed to palmitic acid (PA, 400 μM, 24 h), followed by TAK1 overexpression or knockdown. Macrophage polarization and inflammatory signaling were evaluated by RT-qPCR and Western blotting. Results: Network pharmacology identified 125 overlapping targets within the OCM-related intervention target space. The PPI network contained 108 nodes and 486 edges. AKT1, STAT3, IL6, TP53, and TNF were the top hub genes. TAK1 showed a degree value of 20 and interacted directly with NFKB1, IL1B, and TNF. Enrichment analysis indicated involvement of glucose homeostasis, cardiac contraction, protein serine/threonine kinase activity, insulin signaling, AGE-RAGE signaling, and HIF-1 signaling. In vivo, high-fat diet-induced obesity and OCM were accompanied by increased TAK1 expression and altered cardiac macrophage polarization. In vitro, PA increased TAK1 and CD86 expression and decreased CD163 expression. TAK1 overexpression enhanced iNOS, NF-κB, and IL-12 expression and suppressed Arg1 and IL-10 expression. TAK1 knockdown reversed these changes. Conclusions: TAK1 is positioned within an OCM-related metabolic-inflammatory network and is upregulated during OCM progression. Functional validation suggests that TAK1 contributes to lipid-induced M1 macrophage polarization, in association with NF-κB-related inflammatory signaling.