Pyruvate is an essential fuel for maintaining the tricarboxylic acid (TCA) cycle in the mitochondria. However, the precise molecular mechanism of pyruvate uptake by mitochondrial pyruvate carrier (MPC) is largely unknown. Here, we report that the DNA/RNA-binding protein Y-box binding protein 1 (YBX1) is localized to the mitochondrial inter-membrane space by its C-terminal domain (CTD) in cancer cells. In mitochondria, YBX1 inhibits pyruvate uptake by associating with MPC1/2, thereby suppressing pyruvate-dependent TCA cycle flux. This association, in turn, promotes MPC-mediated glutaminolysis and histone lactylation. Our findings reveal that the YBX1-MPC axis exhibits a positive correlation with metastatic potential, while does not affect cell proliferation in both cultured cells and tumor xenografts. Therefore, the restricted pyruvate uptake into mitochondria potentially represents a hallmark of metastatic capacity, suggesting that the YBX1-MPC axis is a therapeutic target for combating cancer metastasis.

In recent decades, the global prevalence of metabolic syndrome has surged, posing a significant public health challenge. Metabolic disorders, encompassing diabetes, obesity, nonalcoholic fatty liver disease, and polycystic ovarian syndrome, have been linked to alterations in the gut microbiota. Nonetheless, the connection between gut microbiota and host metabolic diseases warrants further investigation. In this review, we delve into the associations between various metabolic disorders and the gut microbiota, focusing on immune responses and bile acid (BA) metabolism. Notably, T helper cells, innate lymphoid cells, macrophages, and dendritic cells have been shown to modulate host metabolism through interactions with intestinal microorganisms and the release of cytokines. Furthermore, secondary BA metabolites, derived from the microbiota, are involved in the pathogenesis of metabolic diseases via the farnesoid X receptor and Takeda G protein-coupled receptor 5. By covering both aspects of this immune system-microorganism axis, we present a comprehensive overview of the roles played by the gut microbiota, microbiota-derived BA metabolites, and immune responses in metabolic diseases, as well as the interplay between these systems.

Precise control of circulating lipid levels is vital in both health and disease. We recently uncovered that bulk lipids, transported by lipoproteins, enter the circulation initially via the coat protein complex II (COPII) in a condensation-dependent manner. Divalent manganese, acting as a signaling messenger, selectively controls COPII condensation to regulate lipid homeostasis in vivo. Here, we present evidence for a manganese-based therapy in murine models of hypolipidemia and hyperlipidemia, aided by advanced in vivo multimodal imaging of atherosclerosis. Dietary titration of manganese supply enables tailored control of circulating lipid levels in whole animals, with no apparent toxicity. Strikingly, elevating the manganese signal through diets could not only effectively treat pathological hyperlipidemia but also further achieve significant reversal of atherosclerotic plaques. Hence, the study provides critical proof-of-principle for a novel therapy for deadly cardiovascular diseases with a potentially broad impact.

Regardless of its anatomical site, adipose tissue shares a common energy-storage role but exhibits distinctive properties. Exploring the cellular and molecular heterogeneity of white adipose tissue (WAT) is crucial for comprehending its function and properties. However, existing single-nucleus RNA sequencing (snRNA-seq) studies of adipose tissue heterogeneity have examined only one or two depots. In this study, we employed snRNA-seq to test five representative depots including inguinal, epididymal, mesenteric, perirenal, and pericardial adipose tissues in mice under physiological conditions. By analyzing the contents of main cell categories and gene profiles of various depots, we identified their distinctive physiological properties. Immune cells and fibro-adipogenic progenitor cells (FAPs) showed dramatic differences among WAT depots, while adipocytes seemed to be conserved. The heightened presence of regulatory macrophages and B cells in pericardial adipose tissues implied their potential contribution to the preservation of coronary vascular function. Moreover, the selective aggregation of pericytes within mesenteric adipose tissue was likely associated with the maintenance of intestinal barrier homeostasis. Using a combination of RNA sequencing and snRNA-seq analysis, the major subpopulations of FAPs derived from these depots determined the site characteristics of FAPs to a certain extent. Our work establishes a systematic and reliable foundation for investigating the heterogeneity of WAT depots and elucidating the unique roles these depots play in coordinating the function of adjacent organs.