{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T06:31:33Z","timestamp":1786516293272,"version":"build-2736575974"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>\n                    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\n                    <jats:italic>de novo<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.3389\/fendo.2026.1901478","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T05:58:36Z","timestamp":1786514316000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic dysfunction-associated steatohepatitis (MASH): intersections with type 2 diabetes and insulin resistance"],"prefix":"10.3389","volume":"17","author":[{"given":"Nick","family":"Giannoukakis","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Pittsburgh School of Medicine","place":["Pittsburgh, PA, United 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