Monocyte bioenergetics: An immunometabolic perspective in metabolic dysfunction-associated steatohepatitis

Monocytes (Mos) are crucial in the evolution of metabolic dysfunction-associated steatotic liver disease (MASLD) to metabolic dysfunction-associated steatohepatitis (MASH), and immunometabolism studies have recently suggested targeting leukocyte bioenergetics in inflammatory diseases. Here, we reveal a peculiar bioenergetic phenotype in circulating Mos of patients with MASH, characterized by high levels of glycolysis and mitochondrial (mt) respiration. The enhancement of mt respiratory chain activity, especially complex II (succinate dehydrogenase [SDH]), is unbalanced toward the production of reactive oxygen species (ROS) and is sustained at the transcriptional level with the involvement of the AMPK-mTOR-PGC-1α axis. The modulation of mt activity with dimethyl malonate (DMM), an SDH inhibitor, restores the metabolic profile and almost abrogates cytokine production. Analysis of a public single-cell RNA sequencing (scRNA-seq) dataset confirms that in murine models of MASH, liver Mo-derived macrophages exhibit an upregulation of mt and glycolytic energy pathways. Accordingly, the DMM injection in MASH mice contrasts Mo infiltration and macrophagic enrichment, suggesting immunometabolism as a potential target in MASH. [Display omitted] •Circulating monocytes (Mos) in patients with MASH show a bioenergetic reprogramming•SDH inhibition in vitro restores MASH Mo bioenergetics, abolishing cytokine production•In mice, energy pathways are upregulated in liver Mo-derived macrophages during MASH•SDH inhibition in vivo reduces Mo infiltration and differentiation in MASH Sangineto et al. investigate the bioenergetics and mitochondrial activity of circulating monocytes in patients with MASH, revealing a hypermetabolic state also identified in liver monocyte-derived macrophages through transcriptomic analysis. Immunometabolic modulation via SDH inhibition attenuates inflammation both in vitro and in vivo, ameliorating MASH.