A Global Perspective on Metabolic Dysfunction-Associated Steatotic Liver Disease: From Molecular Mechanisms to Therapeutic Strategy Innovation.

Cardiovascular disease is the leading cause of mortality in MASLD patients.

• MASLD is driven by metabolic syndrome components including obesity, dyslipidemia, and insulin resistance.
• The review identifies cardiovascular disease as the primary mortality driver, not liver-related complications.
• MASLD mechanisms not only promote hepatic injury but also accelerate atherosclerosis.

MASLD pathogenesis involves multiple interconnected molecular pathways.

• Key pathways include dysregulated de novo lipogenesis, insulin resistance, and mitochondrial dysfunction.
• Additional mechanisms include gut dysbiosis, ferroptosis, and genetic and epigenetic predispositions.
• These mechanisms are described as interconnected rather than acting independently.
• The multifactorial nature of the disease is emphasized as a central challenge for therapeutic development.

MASLD exhibits significant sexual dimorphism influenced by multiple biological factors.

• Sexual dimorphism in MASLD is influenced by physiological differences, sex hormones, genetic factors, and the microbiome.
• The review identifies sexual dimorphism as a notable feature requiring specific consideration in research and treatment.
• Both biological sex differences and hormonal influences are highlighted as contributing factors to differential disease presentation.

Dietary-induced animal models, particularly in rats, are the primary experimental tools for studying MASLD.

• The review states that study of complex MASLD processes 'relies mostly on dietary-induced animal models, particularly in rats.'
• Rat models are described as effectively recapitulating features of the human disease.
• Refinement of preclinical models is identified as essential to better understand and target MASLD.
• The adequacy of current experimental models is discussed in the context of their ability to reflect human disease complexity.

The therapeutic approach for MASLD is shifting from monotherapies toward combination or dual-target strategies.

• The multifaceted nature of MASLD is cited as the rationale for moving beyond single-agent therapies.
• Combination or dual-target strategies are identified as the emerging therapeutic focus.
• This therapeutic transition is described as requiring refinement of preclinical models to enable successful development.
• The shift reflects recognition that no single pathway adequately captures the full disease pathogenesis.

Ferroptosis is identified as one of the key mechanisms contributing to MASLD progression.

• Ferroptosis is listed alongside dysregulated de novo lipogenesis, insulin resistance, mitochondrial dysfunction, gut dysbiosis, and genetic/epigenetic predispositions as a contributing pathway.
• Ferroptosis is described as promoting hepatic injury in the context of MASLD.
• Its inclusion among primary pathogenic mechanisms reflects emerging recognition of iron-mediated cell death in liver disease.

Gut dysbiosis is a key pathogenic mechanism in MASLD that contributes to hepatic injury.

• Gut dysbiosis is identified as one of the interconnected pathways in MASLD pathogenesis.
• The microbiome is also noted as a factor influencing the sexual dimorphism observed in MASLD.
• Gut dysbiosis is presented as both a hepatic injury driver and a modulator of sex-related disease differences.