The nitrate-Sialin axis: a new target for regulation of macrophage metabolic reprogramming and metabolic homeostasis

Metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (T2DM) have emerged as significant global health issues due to alterations in lifestyle and dietary habits [1,2].The inflammatory variant of metabolic dysfunction-associated steatohepatitis (MASH) may result in cirrhosis and hepatocellular carcinoma.The coexistence or exacerbation of T2DM and MASLD increases the risk of cardiovascular and cerebrovascular complications.Notably, T2DM is a key driver of MASLD progression toward advanced fibrosis and cirrhosis.Despite their growing burden, effective disease-modifying interventions remain limited.In the recent issue of Signal Transduction and Targeted Therapy, Li et al. investigate the effects of inorganic nitrate supplementation on macrophage metabolic reprogramming and systemic metabolic homeostasis [3] (Figure 1).Dietary nitrate enhances nitric oxide (NO) bioavailability via the nitrate-nitrite-NO pathway, complementing the classical nitric oxide synthase (NOS) system.Through entero-salivary circulation and enzymatic reduction in blood and tissues, nitrate and nitrite can be converted into bioactive NO.Following recognition of nitrate as a physiological signaling precursor instead of being a dietary risk factor, interest has expanded toward the broader metabolic effects of this anion.Previous studies mostly focused on vascular function and exercise performance.However, there is growing evidence linking dietary nitrate to metabolic regulation.Population-based studies have indicated correlations between circulating nitrate and liver enzymes [4], but other research proposes that vegetable-derived nitrate may confer preventive effects against fatty liver disease [5].In experimental animals, nitrate supplementation mitigates hepatic steatosis, enhances glucose and lipid metabolism, and alleviates age-related metabolic decline [6].These results suggest a context-dependent but potentially beneficial role of nitrate in metabolic equilibrium.In the research of Li et al., the results show that dietary nitrate alleviates MASLD-like symptoms in mice fed cholinedeficient high-fat, methionine/choline-deficient, or Western diets [3].Nitrate alleviates hepatic injury and improves glucose and lipid metabolism.The metabolic health benefits of sodium nitrate were unchanged despite the removal of bacteria-derived NO from mice.This finding challenges the idea that nitrate only works by making NO and suggests a way for nitrate to work without the help of bacteria.