Nitric oxide pathway: Emerging therapeutic strategies for MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 30-40% of the global population, making it the most prevalent chronic liver disorder worldwide. Its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), may advance to fibrosis, cirrhosis, and hepatocellular carcinoma, imposing a substantial socioeconomic and clinical burden. The recent FDA approval of Resmetirom for non-cirrhotic MASH has marked a significant therapeutic milestone; however, the multifactorial nature of MASLD continues to necessitate the identification of complementary therapeutic targets. The nitric oxide (NO) pathway has been increasingly recognized as a context-dependent regulator in MASLD pathogenesis, exhibiting dual and sometimes opposing biological effects. Under physiological conditions, low levels of NO derived from endothelial nitric oxide synthase (eNOS) contribute to hepatic microvascular homeostasis and limit lipid accumulation. In contrast, inducible nitric oxide synthase (iNOS) activity is enhanced during chronic metabolic inflammation, leading to excessive NO production, which may promote nitrosative stress through the formation of reactive nitrogen species including peroxynitrite (ONOO⁻). These processes have been associated with mitochondrial dysfunction, eNOS uncoupling, and progressive tissue injury. Accordingly, a more precise understanding of the spatial, temporal and concentration-dependent regulation of NO signaling is required. This review synthesizes current evidence on the dual role of NO in MASLD and critically evaluates emerging therapeutic strategies targeting this pathway, with the aim of informing future translational research.