Elevated consumption of high-fat diets is increasingly linked to obesity, insulin resistance, and type 2 diabetes, all of which coalesce under the umbrella of metabolic syndrome (MetS). One critical aspect of MetS is Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD), which is heralded by an accumulation of triacylglycerides (TAG) in hepatocytes, with a notable threshold of over 5% triggering disease state recognition. MASLD spans a wide array of histological changes from simple steatosis to the more severe Metabolic Dysfunction-associated Steatohepatitis (MASH), leading potentially to cirrhosis or hepatocellular carcinoma. MASH is marked by steatosis coupled with inflammatory infiltration and hepatocellular ballooning, often accompanied by fibrosis and Mallory's corpuscles.

The genesis of MASLD is multifaceted—predominantly driven by the imbalance between the uptake and synthesis of TAG, sourced from the esterification of fatty acids and de novo lipogenesis from carbohydrates and proteins, and their catabolism through fatty acid oxidation or secretion as VLDLs (very low-density lipoproteins). The excessive accumulation of hepatic lipids underpins a direct link to the onset of hepatic insulin resistance and correlates with the progression towards type 2 diabetes. Numerous mechanisms tie MASLD to insulin resistance, alongside notable inflammatory activity, which exacerbate the disease's progression. Despite these insights, current clinical treatments remain unapproved, underscoring a vital need for investigative research focused on novel molecular targets and therapeutic interventions.

In pursuit of expanding our knowledge and therapeutic arsenal against MASLD, our Research Topic invites contributions that explore new dimensions of the disease, including but not limited to:

• The molecular mechanisms leading to MASLD's onset and trajectory
• The role of insulin resistance in MASLD development
• Interactions between adipose tissue and liver in MASLD
• The contribution of macrophages in hepatic steatosis
• Extracellular vesicles' roles in MASLD onset
• Advanced glycation end products (AGEs) and their impact on MASLD
• Reactive oxygen species (ROS) in liver damage and progression of MASLD
• Molecular pathway impacts on endoplasmic reticulum stress in MASLD
• The interplay between fibrotic and inflammatory pathways in advancing MASLD
• Dietary influences on MASLD development
• Therapeutic targets and drug discovery in MASLD
• Innovative drug targets revealed through molecular research
• Developing combined therapeutic strategies for comprehensive pathway intervention

This scope aims to foster a deeper understanding and innovate treatment approaches, leveraging molecular biology and clinical research to confront this complex condition effectively.

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Frontiers in Pharmacology

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