Background:Oxidized low-density lipoprotein (OxLDL) plays a key role in initiating monocyte activation, glycolytic reprogramming, and pro-inflammatory cytokine production-processes that contribute to aging and progression of age-related diseases such as atherosclerosis and steatohepatitis. Mitochondrial reactive oxygen species (ROS), particularly from complex I, are known modulators of these responses. This study aimed to evaluate the impact of OxLDL on the metabolic and inflammatory responses of primary human monocytes and determine whether co-treatment with site-1 Qo electron leak (S1QEL), a mitochondrial complex I-specific ROS suppressor, could mitigate these effects. Methods:Monocytes were isolated from healthy human donors and treated with OxLDL alone or in combination with S1QEL. Metabolic parameters including extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were measured using the Seahorse XF Analyzer. Pro-inflammatory gene expression (IL1B, CXCL8, IL6, TNF) was assessed using quantitative real-time polymerase chain reaction. Results:OxLDL treatment significantly increased ECAR, indicating enhanced glycolytic activity, without altering mitochondrial respiration (OCR). This metabolic shift was attenuated by S1QEL co-treatment. OxLDL also upregulated IL1B, CXCL8, and IL6 expression, which was significantly reduced by S1QEL. TNF expression remained unchanged across all conditions. Conclusions:S1QEL effectively suppresses both glycolytic reprogramming and pro-inflammatory cytokine expression induced by OxLDL in human monocytes. These findings underscore the role of mitochondrial complex I-derived ROS in monocyte activation and highlight S1QEL as a potential therapeutic agent for targeting inflammation in aging and several age-related diseases.
This viewpoint focuses on core evidence regarding the cross-talk between adipose tissue inflammation and hepatic inflammation that possibly leads to the progression of metabolic dysfunction-associated steatotic liver disease to metabolic dysfunction-associated steatohepatitis, hepatic fibrosis, and cirrhosis. It is highlighted that the adipose tissue and hepatic inflammation increase in parallel with insulin resistance, possibly affecting each other, thereby leading to advanced liver disease. This interplay is partly mediated via adipokines produced by the adipose tissue, hepatokines produced by the liver, and cytokines produced by the immune cells infiltrating both the adipose tissue and the liver.
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a leading cause of hepatocellular carcinoma (HCC), driven in part by oxidative stress-induced immune dysfunction that limits the efficacy of immunotherapy. In a recent study, Yu et al developed a vitamin E-incorporated lipid nanoparticle designed to enhance hepatocyte‑specific mRNA delivery while simultaneously buffering oxidative stress in the hepatic microenvironment. By restoring the activity of the redox‑sensitive phosphatase T‑cell protein tyrosine phosphatase and suppressing signal transducer and activator of transcription (STAT) signaling, this strategy improves metabolic homeostasis, reduces inflammatory signaling, and enhances responsiveness to immune checkpoint blockade. These findings illustrate how rational nanoparticle engineering can integrate therapeutic delivery with microenvironmental reprogramming in chronic metabolic disease.
Inflammatory bowel disease (IBD) defines a group of diseases, including Crohn’s disease and ulcerative colitis, characterized by chronic inflammation of the gastrointestinal tract. Evidence suggests that visceral adipose tissue, particularly its mesenteric component, influences the course of IBD through its immunomodulatory properties. Mesenteric adipose tissue (MAT) is composed of multiple cell types, including adipocytes, preadipocytes, and immune cells, that collectively regulate energy balance and endocrine signaling. MAT is a unique fat depot as it directly connects along most of the intestinal serosa and harbors the arteries, veins, and lymph nodes that support intestinal function. MAT’s placement at the intestinal barrier serves to contain microbial translocation and support the repair of intestinal epithelium. However, inflammation initiated by obesity or IBD renders it maladaptive, triggering an influx of immune cells that, in turn, release proinflammatory adipokines, cytokines, and chemokines, resulting in local and systemic metabolic effects. Clinical data strongly link the accumulation of inflammatory MAT in the pathology of Crohn’s disease through the development of “creeping fat", a fibrotic, immune-rich tissue that shields the inflamed bowel but can also exacerbate the condition. The inflammatory mediators produced by MAT and the mechanisms by which they aggravate IBD are not well understood. This review synthesizes recent advances in the understanding of the cellular complexity of MAT, emphasizing the bidirectional immune crosstalk between the intestine and the mesentery, and exploring how metabolic or microbial stress drives maladaptive transformation. Finally, we highlight therapeutic strategies that may preserve the reparative functions of MAT while limiting fibrogenic remodeling.
