Nitric oxide pathway: Emerging therapeutic strategies for MASLD

Area of Science:

• Hepatology and Metabolic Disorders
• Molecular Biology
• Pharmacology

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health concern, affecting 30-40% of the population.
• Its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), can lead to severe liver conditions like cirrhosis and cancer.
• While new treatments like Resmetirom show promise, the complex nature of MASLD requires identifying additional therapeutic targets.

Purpose of the Study:

• To review the dual role of the nitric oxide (NO) pathway in MASLD pathogenesis.
• To critically evaluate emerging therapeutic strategies targeting NO signaling in MASLD.
• To inform future translational research for MASLD treatment.

Main Methods:

• Literature review synthesizing current evidence on NO signaling in MASLD.
• Analysis of the context-dependent effects of NO, including roles of eNOS and iNOS.
• Evaluation of therapeutic strategies targeting the NO pathway.

Main Results:

• The NO pathway plays a dual role in MASLD: low NO levels (eNOS) support liver health, while excessive NO (iNOS) can promote inflammation and injury.
• iNOS-derived NO contributes to nitrosative stress, mitochondrial dysfunction, and tissue damage in MASH.
• Understanding the spatial, temporal, and concentration-dependent regulation of NO signaling is crucial.

Conclusions:

• The NO pathway presents a complex but promising target for MASLD therapy.
• Targeting NO signaling requires a nuanced approach due to its dual functions.
• Further research into NO modulation could lead to novel complementary treatments for MASLD.