Type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) are both characterized by chronic low-grade inflammation. The role of Th17 and its related cytokines in T2DM and CAD is unclear. Here we investigated the serum levels of five Th17-related cytokines (IL-17, IL-22, MIP-3α, IL-9, and IL-27) in T2DM, CAD, and T2DM-CAD comorbidity patients. IL-22 was found to be elevated in all three conditions. Elevated serum IL-22 was independently associated with the incidence of T2DM and CAD. Conversely, IL-22 was found to protect endothelial cells from glucose- and lysophosphatidylcholine- (LPC-) induced injury, and IL-22R1 expression on endothelial cells was increased upon treatment with high glucose and LPC. Blocking of IL-22R1 with IL-22R1 antibody diminished the protective role of IL-22. Our results suggest that IL-22 functions as a double-edged sword in T2DM and CAD and that IL-22 may be used in the treatment of chronic inflammatory diseases such as T2DM and CAD.

Heart failure is a complex clinical syndrome caused by structural and/or functional cardiac abnormalities. Ventricular remodeling contributes to its progression. Cardiac macrophages regulate inflammation, fibrosis, and tissue repair that drive this process. In this Review, we describe the origins and phenotypic diversity of cardiac macrophages, including both resident and monocyte-derived subsets. In the left ventricle, macrophages respond to ischemia, pressure overload, and metabolic stress. In the right ventricle, they display distinct immune features under pulmonary hypertension and other stress conditions. We further discuss the interactions between macrophages and other cardiac cell types, such as fibroblasts, cardiomyocytes, endothelial cells, and lymphocytes. These interactions shape the immune environment and structural integrity of the myocardium. We also highlight recent advances in single-cell and spatial technologies that reveal chamber-specific macrophage signatures. Finally, we summarize emerging therapeutic strategies targeting macrophages, including pharmacological agents, engineered cell therapies, and nanoparticle-based delivery systems. Together, these insights provide a framework for understanding macrophage-mediated remodeling and for guiding precision immunotherapies in heart failure.

Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than 1000 nuclear-encoded proteins. Transcriptional networks controlling the nuclear-encoded mitochondrial genes remain to be fully elucidated. Here, we show that histone demethylase LSD1 KO from adult mouse liver (LSD1-LKO) reduces the expression of one-third of all nuclear-encoded mitochondrial genes and decreases mitochondrial biogenesis and function. LSD1-modulated histone methylation epigenetically regulates nuclear-encoded mitochondrial genes. Furthermore, LSD1 regulates gene expression and protein methylation of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), which controls the final step of NAD ⁺ synthesis and limits NAD ⁺ availability in the nucleus. Lsd1 KO reduces NAD ⁺ -dependent SIRT1 and SIRT7 deacetylase activity, leading to hyperacetylation and hypofunctioning of GABPβ and PGC-1α, the major transcriptional factor/cofactor for nuclear-encoded mitochondrial genes. Despite the reduced mitochondrial function in the liver, LSD1-LKO mice are protected from diet-induced hepatic steatosis and glucose intolerance, partially due to induction of hepatokine FGF21. Thus, LSD1 orchestrates a core regulatory network involving epigenetic modifications and NAD ⁺ synthesis to control mitochondrial function and hepatokine production.

Several studies have reported associations between specific heavy metals and essential trace elements and acute myocardial infarction (AMI). However, there is limited understanding of the relationships between trace elements and AMI in real-life co-exposure scenarios, where multiple elements may interact simultaneously. This cross-sectional study measured serum levels of 56 trace elements using inductively coupled plasma mass spectrometry. We identified individual trace elements linked to AMI using four feature selection methods and evaluated their associations with AMI prevalence and severity through multiple-element logistic regression. Restricted cubic spline analysis was employed to examine non-linear associations. Additionally, we explored the associations between trace element mixtures and AMI prevalence and severity using Bayesian kernel machine regression (BKMR) and element risk score (ERS). Finally, we investigated the potential mechanisms linking trace element exposure to AMI. We detected stable positive associations and linear relationships between Cu and Rb and AMI prevalence and severity. Furthermore, lower Fe concentrations were associated with higher AMI prevalence, while higher Sb concentrations were linked to greater AMI severity. Both BKMR and ERS models indicated positive associations between trace element mixtures and AMI prevalence and severity. Mediation analysis suggested that high-sensitivity C-reactive protein partially mediated the associations between trace elements and AMI prevalence and severity. We provide the first epidemiological evidence of the associations between serum trace element mixtures and AMI prevalence and severity. Under conditions of trace element co-exposure, Cu, Rb, Fe, and Sb were closely associated with AMI. Additionally, our results indicate that hsCRP (inflammation) may be a potential mechanism linking trace elements to AMI.