MASH: the nexus of metabolism, inflammation, and fibrosis
Gregory R. Steinberg, Andre C. Carpentier, Dongdong Wang
Gregory R. Steinberg, Andre C. Carpentier, Dongdong Wang
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Review Series

MASH: the nexus of metabolism, inflammation, and fibrosis

Abstract

Metabolic dysfunction–associated steatohepatitis (MASH) is a progressive form of liver disease characterized by hepatocyte injury, inflammation, and fibrosis. The transition from metabolic dysfunction–associated steatotic liver disease (MASLD) to MASH is driven by the accumulation of toxic lipid and metabolic intermediates resulting from increased hepatic uptake of fatty acids, elevated de novo lipogenesis, and impaired mitochondrial oxidation. These changes promote hepatocyte stress and cell death, activate macrophages, and induce a fibrogenic phenotype in hepatic stellate cells (HSCs). Key metabolites, including saturated fatty acids, free cholesterol, ceramides, lactate, and succinate, act as paracrine signals that reinforce inflammatory and fibrotic responses across multiple liver cell types. Crosstalk between hepatocytes, macrophages, and HSCs, along with spatial shifts in mitochondrial activity, creates a feed-forward cycle of immune activation and tissue remodeling. Systemic inputs, such as insulin-resistant adipose tissue and impaired clearance of dietary lipids and branched-chain amino acids, further contribute to liver injury. Together, these pathways establish a metabolically driven network linking nutrient excess to chronic liver inflammation and fibrosis. This Review outlines how coordinated disruptions in lipid metabolism and intercellular signaling drive MASH pathogenesis and provides a framework for understanding disease progression across tissue and cellular compartments.

Authors

Gregory R. Steinberg, Andre C. Carpentier, Dongdong Wang

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Figure 3

Targets in pathways contributing to elevated DNL and ceramide production in MASH.

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Targets in pathways contributing to elevated DNL and ceramide production...
Delivery of diet-derived FAs, amino acids, fructose, and glucose to the liver supplies carbon for hepatic DNL. Both white and brown adipose tissues function as metabolic sinks for FAs and BCAAs, which also contribute carbon to DNL. GLP -1R agonists reduce food intake via central mechanisms and improve adipose tissue insulin sensitivity, reducing steatosis and MASH. DNL is initiated when excess substrate availability via FAO, carbohydrates, and amino acids converges at the TCA cycle and increases mitochondrial citrate levels. The citrate isotransporter (SLC25A1) exports excess citrate to the cytosol, where it is converted to acetyl-CoA by ATP-citrate lyase (ACLY). Gut microbiome–derived ethanol can also contribute to the hepatic acetyl-CoA pool via ACSS2. Acetyl-CoA may translocate to the nucleus and modulate gene expression programs related to DNL. Nuclear receptors such as FXR, THRβ, and PPAR also regulate gene expression to inhibit DNL, promote FAO, and suppress transcriptional regulators, including ChREBP and SREBP-1c, which both drive expression of DNL enzymes. FXR, THRβ, and PPAR agonists improve MASH by simultaneously inhibiting DNL and enhancing FAO. Acetyl-CoA is also a precursor for cholesterol synthesis, a process closely linked to liver inflammation and fibrosis. Most cytosolic acetyl-CoA is converted to malonyl-CoA and then to FAs. Targeting key nodes in this pathway — including inhibition of the citrate isotransporter, ACLY, ACC, or FAS or activation of AMPK — suppresses DNL and ameliorates hepatic steatosis. Additionally, inhibition of DGAT2 and activation of SCD1 reduces triglyceride synthesis, thereby attenuating DNL and improving MASH. Ceramides derived from FAs activate the NLRP3 inflammasome in macrophages and contribute to HSC activation. Furthermore, ER stress and mitochondrial-derived ROS activate apoptosis signal-regulating kinase 1 (ASK1), which promotes HSC activation and drives liver fibrosis. ASK1 inhibition has been shown to improve hepatic inflammation and fibrosis. WAT, white adipose tissue; BAT, brown adipose tissue; KHK, ketohexokinase; G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; TAG, triacylglycerol; DGAT2, diacylglycerol O-acyltransferase 2; DAG, diacylglycerol; UFA, unsaturated fatty acids; SCD1, stearoyl-CoA desaturase 1; FAS, fatty acid synthase; ACC, acetyl-CoA carboxylase; HMG-CoA, 3-hydroxy-3-methylglutaryl–CoA; HMGCR, 3-hydroxy-3-methylglutaryl–CoA reductase; SPT, serine palmitoyltransferase; ACSS2, acetyl-CoA synthetase.