Nick Giannoukakis
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.