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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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 4

Impaired FAO and mitochondrial dysfunction in MASH.

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Impaired FAO and mitochondrial dysfunction in MASH. (A) Megamitochondria...
(A) Megamitochondria are a hallmark of MASH. Impaired mitophagy contributes to mitochondrial structural abnormalities in the livers of individuals with MASH, leading to reduced FAO. Fasting promotes interactions between the ER and mitochondria in periportal hepatocytes. Fasting also enhances mitochondria–lipid droplet interactions, which are increased during early MASLD but decline as fibrosis progresses. Genetic variants, such as TM6SF2, MBOAT7, and PNPLA3, promote mitochondrial dysfunction, which is characterized by swollen, fragmented cristae, and impaired bioenergetic capacity. (B) Dysfunctional mitochondria exacerbate liver injury by generating incomplete oxidation byproducts, including ROS, lactate, and succinate. Fructose metabolism further contributes to mitochondrial oxidative stress by generating uric acid, which depletes glycine and lowers levels of glutathione (GSH), the primary cellular antioxidant responsible for maintaining redox homeostasis. This oxidative imbalance activates proinflammatory and fibrogenic signaling pathways, including NF-κB and TGF-β/SMAD. A key feature of impaired oxidative phosphorylation is elevated lactate production. In Kupffer cells and monocyte-derived macrophages, lactate induces histone lactylation at H3K18la, upregulating fibrogenic genes such as CD86 and iNOS. In HSCs, activation via hedgehog or Wnt/β-catenin signaling enhances lactate utilization to fuel differentiation into myofibroblasts. The TCA cycle intermediate succinate binds to succinate receptor 1 (SUCNR1/GPR91), activating MEK/ER/c-Jun and PI3K/Akt/IKK/NF-κB pathways to promote inflammation. Succinate also stabilizes hypoxia-inducible factor 1α (HIF-1α), stimulating macrophage recruitment and the production of proinflammatory cytokines, including IL-6 and TNF.