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Metabolic dysfunction-associated steatohepatitis (MASH): intersections with type 2 diabetes and insulin resistance
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DOI：10.3389/fendo.2026.1901478.png)
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Abstract
En 中文
Metabolic dysfunction-associated fibrotic/steatotic liver disease (MASLD) and its progressive inflammatory form; metabolic dysfunction-associated steatohepatitis (MASH); are increasingly recognized as disorders of failed metabolic; immune; vascular; and reparative integration rather than as simple hepatic fat accumulation. Hepatic insulin resistance is a central pathogenic lesion because it permits persistent gluconeogenesis while maintaining or amplifying de novo lipogenesis; thereby linking adipose tissue dysfunction; lipotoxic hepatocyte stress; innate immune activation; endothelial injury; and fibrogenesis. This review provides an integrated framework for MASLD/MASH pathogenesis by discussing concrete preclinical and clinical examples across hepatic insulin resistance; inflammatory amplification; neutrophil biology; CXCR1/2 pathways; triglycerides; and peroxisome proliferator-activated receptor biology. Furthermore; it introduces how sphingosine-1-phosphate signaling; mesenchymal stromal cell biology; and endogenous stromal repair failure could be a functional part of this overall integration of dyslipidemia/insulin resistance-driven/conditioned MASLD/MASH. For each axis; the review summarizes observed preclinical and clinical outcomes; identifies limitations that have constrained translation; and proposes possible next steps for biomarker-enriched therapeutic development. The central conclusion is that future MASLD/MASH trials should move beyond histologic staging alone and toward biologically endotyped development programs that match metabolic; neutrophil-dominant; stromal-fibrotic; vascular; or sphingolipid-centric mechanisms to rational monotherapy or combination strategies.
Keywords:
sphingosine-1-phosphate
dyslipidemia
neutrophils
MASLD
MASH
liver fibrosis
mesenchymal stromal cells
hepatic insulin resistance
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4.6
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1.9W
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6.4W
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