Pathogenesis of metabolic dysfunction-associated steatotic liver disease and donor liver damage

Chuheng Gou; Wenjie Zhang; Hao Xu; Hong Zhang; Rui Ding; Xuan Zhang

doi:10.1016/j.iliver.2025.100195

. 2025 Sep 13;4(4):100195. doi: 10.1016/j.iliver.2025.100195

Pathogenesis of metabolic dysfunction-associated steatotic liver disease and donor liver damage

Chuheng Gou ^1,^a, Wenjie Zhang ^1,^a, Hao Xu ¹, Hong Zhang ¹, Rui Ding ^1,^⁎, Xuan Zhang ^1,^⁎

PMCID: PMC12528891 PMID: 41113624

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than a quarter of adults worldwide. MASLD is associated with severe medical burdens and leads to further reduction of the donor pool for liver transplantation. However, there is a lack of systematic evaluation of the pathogenesis of MASLD development and MASLD graft damage. As a multisystem disorder, the pathogenesis of MASLD is closely related to genetics, metabolic and endocrine disorders, imbalanced intestinal flora, abnormal hepatocyte homeostasis, and hepatic inflammation. Mutations or single nucleotide polymorphisms and epigenetic modifications in multiple genes increase a person's susceptibility to developing MASLD. Lipid accumulation is a central pathogenic driver, and intestinal microbiota and endocrine disorders can exacerbate steatosis and inflammation. These issues cause endoplasmic reticulum stress in hepatocytes, leading to apoptosis and promoting the recruitment and activation of immune cells. Ultimately, hepatic stellate cells are activated, resulting in liver fibrosis. These molecular and pathological changes are important causes of why a MASLD donor liver is likely to suffer ischemia-reperfusion injury and cold ischemic injury. Lipid deposition, microcirculation disturbance, and inflammation in the MASLD donor liver exacerbates ischemia-reperfusion-related damage. During transplantation, cold ischemia time should be minimized, and machine perfusion implemented and treatments for MASLD used after transplantation to protect the graft. This systematic review describes the pathogenesis of MASLD and the mechanism of MASLD donor liver damage to potentially increase the use of MASLD donor livers and provide strategies to preserve organ function.

Keywords: Metabolic dysfunction-associated steatotic liver disease (MASLD), Non-alcoholic fatty liver disease (NAFLD), Hepatocyte homeostasis imbalance, Steatotic donor liver, Ischemia-reperfusion injury (IRI)

1. Introduction

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and affects 25% of adults worldwide.¹ NAFLD is predicted to become the leading reason for liver transplantation in 2030.² In 2023, NAFLD was renamed “metabolic dysfunction-associated steatotic liver disease” (MASLD) by the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver, and the Asociación Latinoamericana para el Estudio del Hígado.³ This pivotal nomenclature change replaces exclusionary diagnostic criteria with pathophysiology-focused terminology, emphasizing the central role of metabolic dysfunction, such as diabetes, obesity, and hyperlipidemia, in disease management.⁴ Notably, a new category called MetALD was introduced to describe men and women with MASLD and weekly alcohol consumption of 140–350 g and 210–420 g, respectively.⁵ MASLD remains highly consistent with the definition of NAFLD; more than 98% of NAFLD patients meet the diagnostic criteria for MASLD,⁶^,⁷ and the research data and results on NAFLD remain applicable to MASLD.⁸ Discussion is on-going regarding whether to accept donor livers from patients with MASLD, as an important part of marginal liver grafts, to expand the donor pool. The shortage of donor livers is an important obstacle in liver transplantation. In China, almost 20,000 people await liver transplantation annually, but less than 6000 undergo the procedure.⁹ This issue is driving efforts to use MASLD donor livers and identify methods to reduce damage. In this review, studies of MASLD or NAFLD and MASLD donor liver damage are summarized, and the pathogenesis of the incidence and development of MASLD is discussed in depth. The mechanism of MASLD donor liver damage is also discussed to provide information on the treatment of MASLD and the use of MASLD donor livers. This work suggests post-transplant targeted metabolic therapy as a pivotal component in MASLD donor liver protection; thereby, establishing novel avenues for research on MASLD graft protection.

2. Pathogenesis of MASLD

MASLD is associated with metabolic disorders and characterized by triglyceride accumulation in >5% of the liver in patients without alcohol abuse.¹⁰ The degree of MASLD ranges from steatosis to hepatitis (metabolic dysfunction-associated steatohepatitis, MASH) and finally to liver fibrosis and cirrhosis, which eventually lead to hepatocellular carcinoma.¹¹ The development of MASLD is closely related to genetics and various metabolic disorders, including obesity, type 2 diabetes mellitus (T2DM), and hyperlipidemia.¹²^,¹³ Although multiple theories are recognized, the pathogenesis of MASLD is unclear.

In 1998, the two-hit hypothesis was proposed, as follows: the first hit is insulin resistance leading to hepatic lipid deposition, and the second hit is oxidative stress and lipid peroxidation leading to damage to hepatocyte mitochondria and genetic material, which causes apoptosis and inflammation.¹⁴ This theory was developed in subsequent studies and emphasizes the interaction of multiple factors, namely genetics, triglyceride metabolism disorders in hepatocytes, insulin resistance, and imbalanced intestinal flora.¹⁵ Genetic susceptibility constitutes the foundational background, while dysregulated lipid metabolism serves as the primary pathogenic driver. Hormonal dysregulation acts as a disease amplifier, and imbalanced intestinal flora as an extrinsic trigger. Hepatocyte homeostasis disruption represents the critical transition point, with sustained inflammation and progressive fibrosis forming the terminal pathological pathways in MASLD progression. When the initial hit exceeds compensatory capacity, sequential amplification of downstream factors is triggered. These factors interact and gradually lead to MASLD.

2.1. Genetics

The risk of MASLD is closely related to genetics (Fig. 1A), which appears as familial aggregation, with a genetic risk of 35%–61%.¹⁶ Mutations or single nucleotide polymorphisms (SNPs) in multiple genes are associated with the heritability of MASLD. Mutations in TMPO cause lamella-associated polypeptide 2 truncation mutations, which promote fat accumulation in hepatocytes.¹⁷ PNF13 promotes the ubiquitin-dependent degradation of the stimulator of interferon genes protein, regulates hepatic innate immune activation, and inhibits hepatic lipid deposition and inflammatory responses.¹⁸ SNPs in PNPLA3, TM6SF2, GCKR, HSD17B13, MBOAT7, SOD2, irisin, MERTK, ApoC3, MTARC1, GPAM, and Ephb2 are also associated with the risk of MASLD.¹⁶^,19, 20, 21, 22 SNPs in these genes lead to lipid accumulation and fibrosis in the liver by affecting physiological processes, such as intrahepatic lipid metabolism and transport, lipid synthesis, insulin resistance, oxidative stress, and activation of hepatic stellate cells (HSCs).¹⁶^,23, 24, 25, 26, 27 Genetic polymorphisms in PNPLA3, TM6SF2, GCKR, HSD17B13, MBOAT7, and irisin are clinically useful for stratifying MASLD risk.²¹^,28, 29, 30 Furthermore, oligonucleotide-based therapies targeting PNPLA3 and HSD17B13 have advanced to clinical trials, showing important potential for ameliorating MASLD pathogenesis.²² Genes associated with MASLD are enriched in lipid metabolism and HSC activation pathways, consistent with the pathophysiological processes.¹⁹ In other words, genes on pathways involved in glucose and lipid metabolism and fibrosis are potential targets affecting susceptibility to MASLD. These targets underpin both risk stratification and precision medicine approaches for MASLD.

Epigenetic modifications also play an essential role in the development of MASLD. DNA demethylation, histone methylation, non-coding RNA expression, and methylation-related protein (DNA methyltransferase 1 and PRDM/Riz1) expression are associated with non-alcoholic steatohepatitis in mice.²³^,³¹ High-fat diets upregulate DNA methyltransferase expression through increased chromatin accessibility and reduced ubiquitin-mediated proteasomal degradation. This epigenetic dysregulation promotes hypermethylation of promoters in metabolically critical genes (Klb, ApoB), suppressing their transcription and consequently impairing hepatic fatty acid oxidation and transport pathways.³²^,³³ RNA methylation is essential for stable RNA regulation of lipid metabolism-related genes, impacting hepatic lipid synthesis and deposition.¹⁶ FTO-mediated N6-methyladenosine demethylation enhances the translational efficiency of SREBP-1c, facilitating its proteolytic maturation and nuclear translocation to promote hepatic de novo lipogenesis. Conversely, reduced N6-methyladenosine methylation of peroxisome proliferator-activated receptor alpha (PPARα) mRNA accelerates its decay through YTH domain family 2-dependent degradation, impairing fatty acid β-oxidation pathways.³⁴^,³⁵

Genetic susceptibility underlies MASLD development. Genetic variants and epigenetic alterations modulate lipid metabolism, mitochondrial function, and inflammatory responses, predisposing individuals to subsequent metabolic hits and determining the rate of MASLD progression. Gene therapies directed against the susceptibility genes, PNPLA3 and HSD17B13, have advanced to Phase II clinical trials.³⁶

2.2. Lipid metabolism disorders

The accumulation of adipose in the liver is the core element contributing to MASLD (Fig. 1B). The liver is the center of fatty metabolism, where triglycerides are synthesized, oxidatively decomposed, absorbed, and transported.³⁷ Under physiological conditions, there is no marked fatty accumulation in the liver. However, in the livers of patients with MASLD, adipose deposition results from dietary intake, de novo lipogenesis (DNL), and serum fatty acid esterification, which favors lipogenesis, rather than lipolysis.¹⁹

Among the sources of hepatic fat accumulation, dietary intake accounts for approximately 15%, DNL accounts for 15%–40%, and serum fatty acid esterification accounts for approximately 59%.¹⁹ Increased energy intake leads to a relative deficiency in the ability of the liver to transport and decompose carbohydrates and fats via very-low-density lipoproteins (VLDL), which leads to the accumulation of carbohydrates and fats in the liver.¹⁶ Carbohydrates, such as sucrose and fructose, activate DNL in the liver and generate triglycerides that are stored in hepatocytes.³⁸ Excessive intake of fatty acids, particularly saturated fatty acids, significantly increases the degree of hepatic steatosis.³⁹ Sucrose, fructose, and saturated fatty acids, abundant in Western diets, have been shown in several studies to cause fat deposition and the development of MASLD.³⁹^,⁴⁰ Western diet feeding has been used to build a mouse model of MASLD.⁴⁰ In addition to diet, white adipose tissue, where lipid is decomposed in obesity and insulin resistance, is an essential source of fatty acids in serum, producing free fatty acids that are transported into hepatocytes, increasing lipid deposition.¹⁶^,³⁷^,⁴¹ Additionally, changes in the levels of inflammatory factors (e.g., tumor necrosis factor alpha (TNFα), interleukin (IL)-1b and others) and adipokines (e.g., leptin, adiponectin, resistin, neuregulin 4) secreted by white adipose tissue can affect hepatic metabolic function and the process of steatosis by promoting insulin resistance and altering hepatic and systemic metabolic homeostasis.¹⁶^,⁴²

Hepatic lipid secretion also plays an important role in the development of MASLD. Because excess triglycerides in the liver are transported to the plasma via VLDLs, disturbed secretion of VLDLs leads to excessive accumulation of hepatic lipids.⁴³ In early and mid-term MASLD, DNL drives an increasing concentration of substrate triglyceride, regulating VLDL synthesis. Moreover, insulin negatively regulates the production and secretion of VLDLs by controlling MTTP expression and apolipoprotein B (APOB) translation and degradation. Another reason for hyperlipidemia is that insulin resistance increases VLDL secretion. In late MASLD, VLDL secretion decreases because of endoplasmic reticulum (ER) stress, leading to decreased APOB secretion, which is accompanied by massive hepatocyte death and loss of function.³⁷ Therefore, in the development of MASLD, VLDL production acts as a self-protective mechanism and reduces the rate of fatty accumulation in the liver.

Lipid metabolism disorders constitute the first hit and are a central pathogenic driver in MASLD development. Increased lipid production and decreased catabolism and translocation collectively promote hepatic lipid accumulation. This process generates lipotoxic mediators that trigger downstream cellular injury cascades. Therefore, the AASLD recommends lifestyle intervention and omega-3 fatty acid supplementation for all stages of MASLD. Fibroblast growth factor 21 analogs, acetyl-CoA carboxylase inhibitors, farnesoid X receptor (FXR) agonists, and fatty acid synthase inhibitors have all been shown in clinical trials to modulate lipid metabolism to reduce hepatocyte lipid deposition.⁴⁴^,⁴⁵

2.3. Endocrine disorders

There are complex interactions between the liver and many endocrine axes, of which studies related to insulin have received the most attention (Fig. 1C). The development of MASLD is strongly associated with T2DM; approximately 55.5% of people worldwide with T2DM also have NAFLD.⁴⁶ Insulin resistance, the primary mechanism of T2DM, is considered an initial factor in the development of NAFLD.¹² The central mechanism by which insulin resistance promotes MASLD is the development of hyperglycemia and compensatory hyperinsulinemia, increased breakdown of peripheral lipid particles (chylomicrons and low-density lipoproteins), and increased FFA concentrations, leading to increased hepatic DNL.¹⁶^,⁴⁷ MASLD also promotes insulin resistance. High-fat diets lead to sn-1, 2- diacylglycerol accumulation in the liver, activating protein kinase Cε. This activation results in threonine phosphorylation at position 1160 of insulin receptor tyrosine kinase, ultimately leading to the development of insulin resistance.¹⁶^,⁴⁸

In addition to insulin, abnormalities in multiple hormones affect the course of MASLD. Somatropin diminishes visceral adiposity synthesis and triglyceride accumulation. Additionally, insulin-like growth factor-I can induce HSC apoptosis and reduce liver fibrosis.⁴⁹ The prevalence of MASLD in adult patients with growth hormone deficiency is higher than that in the average person.⁴⁹ Thyroxine increases basal metabolism and protein anabolism and stimulates hepatic lipogenesis and lipolysis through thyroxine receptors α and β, while thyroid-stimulating hormone can induce hepatic steatosis.⁵⁰ Studies have shown that patients with hypothyroidism and elevated thyroid stimulating hormone concentrations have a higher risk of NAFLD progression.⁵⁰ Corticosteroids are well-known for their relationship with weight gain and insulin resistance. However, studies have found that their levels are not significantly associated with the development of MASLD, although there is a positive association between aldosteronism and MASLD.⁵¹ Prolactin inhibits fatty acid synthase activity in adipose tissue and decreases hepatic fat accumulation by reducing cluster of differentiation (CD)36 expression.⁵² However, clinical studies have found that prolactin levels in men are not associated with the incidence of MASLD, while too high or too low prolactin levels in women increases the risk of MASLD.⁵¹ Among the sex hormones, androgens are a protective factor for MASLD in men, and estrogen can improve hepatic steatosis in women. This explains why polycystic ovary syndrome, ovariectomy, and menopause lead to an increased incidence of MASLD in women.⁵¹ Adipokines are an emerging research area and play an important role in the fatty tissue–liver axis communication. For example, physiological levels of leptin promote fat mobilization, while high levels promote liver fibrosis; adiponectin can reduce steatosis, inflammation, and liver fibrosis; and ghrelin-releasing peptide promotes and stimulates appetite, which leads to obesity but can suppress hepatic lipid metabolism disorders, oxidative stress, apoptosis, and inflammation.⁵³ Furthermore, resistin, retinol-binding protein 4, and fatty acid-binding protein all have effects on NAFLD progression.⁵³

Endocrine disorders, most notably insulin resistance, can act as either an initiating factor or as a disease amplifier in MASLD development. As a first hit or a secondary consequence of other pathological hits, endocrine disorders exacerbate hepatic lipid deposition and disrupt cellular homeostasis. Thyroid hormone receptor beta agonists (e.g., resmetirom, which is the first US Food and Drug administration-approved MASLD therapy) and anti-diabetic agents targeting PPAR signaling (e.g., pioglitazone), glucagon-like peptide 1 receptors (e.g., exenatide and semaglutide), and sodium-glucose cotransporter-2 inhibitors (e.g., empagliflozin) were effective in patients with MASLD in Phase IV clinical trials.⁵⁴

2.4. Intestinal flora imbalances

As an important component of the gut–liver axis, the intestinal flora also participates in the pathogenesis of MASLD (Fig. 1D).⁵⁵ Ruminococcus, Streptococcus, Holdemania, Blautia, and Lactobacillus were found to enrich the gut of patients with MASLD.⁵⁶ The intestinal flora aids food digestion and transformation, participates in energy metabolism and the immune response, and maintains homeostasis, which can cause insulin resistance and leads to the progression of MASLD.⁵⁷ This results from fermentation of the sugar that cannot be directly absorbed, changing intestinal permeability, bile acid metabolism, translocation of bacterial metabolites, and activation of inflammation.⁵⁷ Imbalances in the intestinal flora, such as decreased numbers of Bacteroides, is closely related to changes in bile acid homeostasis, which can inhibit the pathway activation of FXR and bile acid receptor TGR5 by bile acids.⁵⁷^,⁵⁸ Additionally, hepatotoxic metabolites produced by intestinal flora (including trimethylamine, ammonia, trimethylamine N-oxide, and endogenous alcohol) are transported to the liver via the portal vein, which activates Kupffer cells and promotes intrahepatic inflammation and fibrosis.⁵⁷ Lipopolysaccharides from bacteria can activate Toll-like receptor 4 (TLR4), which promotes the differentiation of naïve CD4⁺ T cells into T-helper 17 (Th17) cells and a proinflammatory state in the body.⁵⁹ Similarly, bacterial flagella can contribute to MASLD progression by causing inflammasome activation via activating pattern recognition receptor (PRR), leading to hepatic inflammatory responses.⁶⁰

Intestinal flora imbalances represent an extrinsic pathogenic hit. Bacterial metabolites derived from dysbiotic microbiota promote insulin resistance and activate liver-resident immune cells via the portal circulation. Modification of gut microbiota via antibiotics, fecal microbiota transplantation, or probiotic formulations ameliorated dysbiosis and effectively slowed MASLD progression in randomized controlled trials.⁶¹

2.5. Disrupted hepatocyte homeostasis

The core pathological changes in MASLD are hepatocellular lipid deposition, cell death, and hepatic fibrosis. Lipids accumulate in the liver initially without inflammation.⁶² Cumulative pathological hits progressively disrupt hepatocellular homeostasis (Fig. 1E). As lipids accumulate, some substances with lipotoxicity, such as free cholesterol and saturated fatty acids (palmitate, ceramide, and lysophosphatidylcholine), exacerbate the progression of MASLD as the main trigger for conversion to the inflammatory stage.⁶³ Ceramide induces ER stress by causing calcium overload, which activates the unfolded protein response (UPR) via the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α)/activating transcription factor 4 (ATF4) pathway. As a result, C/EBP homologous protein (CHOP) is upregulated, leading to apoptosis. In this state, both cleavage and nuclear translocation of ATF6 are activated, inducing the release of pro-inflammatory extracellular vesicles via the inositol-requiring enzyme 1 alpha (IRE1α)/X-box binding protein 1 (XBP1) pathway, which promotes hepatic inflammatory responses.⁶³^,⁶⁴ Lysophosphatidylcholine can also play a role in ER stress by promoting phosphorylation of eIF2α and activation of c-Jun N-terminal kinase, which leads to apoptosis.⁶⁵^,⁶⁶ In contrast, diacylglycerols drive insulin resistance in hepatocytes by affecting signal transduction associated with the insulin receptor. Mitochondria produce more reactive oxygen species (ROS) during fatty acid oxidation, leading to mitochondrial dysfunction and oxidative stress. This inhibits insulin signaling by activating the degradation of I-κB, IKKβ, and c-Jun N-terminal kinases; thereby, worsening insulin resistance.⁴²

In addition to lipotoxic substances, hyperlipidemia, inflammation, viruses, and drugs can induce ER stress.⁶⁷ These stresses dissociate glucose-regulated protein 78 from three ER transmembrane receptors (PERK, IRE1α, and ATF6) and activate their respective downstream pathways to aid protein folding and regulate metabolism and protein expression, adapting to the UPR.⁶⁸ Among them, activation of the IRE1α/XBP1 axis upregulates lipogenic genes (e.g., DGAT2, SCD), and IRE1α is a crucial regulator of VLDL secretion; VLDL deletion inhibits VLDL secretion.⁶⁹ The PERK-eIF2α-ATF4 axis also regulates lipogenesis and steatosis; eIF2α phosphorylation decreases lipid accumulation, and ATF6α promotes fatty acid oxidation by helping PPARα transcription and decreases fat synthesis by inhibiting SREBP2 transactivation, which improves steatosis.⁶⁷ ER stress that reduces steatosis is protective for MASLD in the short-term. However, chronic ER stress in MASLD damages hepatocytes, which leads to sustained calcium release, mitochondrial membrane damage, and ROS generation and release. PERK/IRE1α activates nuclear factor kappa B (NF-κB) and promotes proteotoxicity and inflammation, leading to pyroptosis and apoptosis. CHOP upregulates transcription of the pro-apoptotic protein BH3 and inhibits the anti-apoptosis pathway, BCL2/BCLXL, inducing hepatocyte death.⁶⁷^,⁷⁰ Upregulation of CHOP coupled with downregulation of Nrf2 during the UPR synergistically drives oxidative stress by exacerbating ROS production.

Cellular decompensation represents a pivotal transition in the progression from MASLD to MASH. ER stress, mitochondrial dysfunction, oxidative stress, impaired autophagy, and disrupted calcium homeostasis collectively drive hepatocyte injury and amplify pro-inflammatory signaling cascades; thereby, initiating hepatic fibrogenesis. To address these pathophysiological mechanisms, the AASLD recommends vitamin E as antioxidant therapy for MASLD.⁷¹ Separately, an apoptosis signal-regulating kinase 1 inhibitor has demonstrated efficacy in reducing hepatic steatosis in a Phase II clinical trial.⁴⁴

2.6. Hepatic inflammation and fibrosis

MASLD progression results in liver inflammation and fibrosis, and MASH.³ Progression can be roughly divided into three phases (Fig. 1F): (1) tissue-resident immune cells monitor hepatocyte stress and secrete pro-inflammatory factors; (2) myeloid pro-inflammatory cells are recruited and trigger inflammation by releasing cytokines, such as TNF, transforming growth factor beta, and IL-1β; and (3) monocytes and lymphocytes, including CD8 T cells, Th17 cells, and B cells, are recruited and cause chronic inflammation, HSC activation, and fibrosis.⁷²

Initially, hepatocytes undergo lipid accumulation in a stressed state, increasing the expression of MICA and MICB.⁷³ γδ T cells, mucosal-associated invariant T (MAIT) cells, and dendritic cells (DCs) residing in a thin area between hepatocytes and endothelial cells, known as the Disse space, initially detect changes in hepatocytes and trigger the inflammatory response.⁷² γδ T cells, as innate immune cells, are activated through NKG2D interacting with the MICA or MICB ligands on hepatocytes. This increases the expression of IL-17A and upregulates chemokines CXCL1 and CXCL2 produced by hepatocytes, which leads to recruitment of myeloid pro-inflammatory cells and activation of a cascade of inflammatory responses.⁷³^,⁷⁴ The role of MAIT cells in the progression of MASLD is unclear. MAIT cells aggravated liver fibrosis by regulating macrophage polarization in a methionine/choline-deficient diet mouse model⁷⁵ but not in a high-fat diet model.⁷³ DCs play an important role in the inflammatory response to MASLD. The proliferation rate of DCs increases in mouse models of non-alcoholic steatohepatitis and XCR1⁺ type 1 conventional DCs, which are significantly enriched. Excess conventional type 1 DCs promote liver inflammation and fibrosis by activating T- and natural killer (NK) cells and recruiting neutrophils.⁷⁶

The second phase of hepatic inflammation primarily involves the activation of tissue-resident Kupffer cells and the recruitment of myeloid cells, such as monocytes and granulocytes, that produce inflammatory factors.⁷² Intrahepatic macrophages can be activated through multiple pathways. For example, degenerated hepatocytes produce chemokines (CCL family and CXCL family) and extracellular vesicles that are chemotactic for macrophages and pro-inflammatory. Another pathway is that Kupffer cells sense free lipids via PRR and scavenger receptors and are activated and participate in lipid engulfment.⁷⁷ Furthermore, imbalances in the intestinal flora in MASLD leads to translocation of bacterial lipopolysaccharide into the liver, binding to CD14 on Kupffer cells and activating them.⁷⁸ Additionally, galectin-3 is markedly upregulated in MASH, which enhances nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome activation by binding to cell surface TLR4 and promoting NF-κB-dependent transcription. Subsequent inflammasome assembly triggers caspase-1 cleavage, driving IL-1β maturation and facilitating M1 macrophage polarization.⁷⁹ TNF-α and IL-1β released by Kupffer cells activate HSCs and liver sinusoidal endothelial cells. This induces the upregulation of chemokines (e.g., CCl2, CCl7, CXCL10, platelet factor 4) and adhesion molecules (e.g., vascular cell adhesion molecule 1, E-selectin, intercellular adhesion molecule 1).⁸⁰^,⁸¹ Additionally, M1 polarization of liver macrophages is potentiated by IL-17 signaling from hepatic γδ T cells.⁸² Expression and phosphorylation of p38α drives NF-κB nuclear translocation and inflammasome priming, amplifying pro-inflammatory responses in MASH.⁸³ Overall, macrophage activation contributes to the progression of MASLD, but some macrophages phagocytose lipids and relieve inflammation.⁷⁷ Compared with Kupffer cells, which reside in the liver, monocyte-derived macrophages cause more intense inflammation.⁸⁴ Macrophages secrete inflammatory factors, such as TNF-α, IL-6, TL-1β, and IL-12, via the activation of TLR4/IKK, which promote lipid synthesis and accumulation and induce hepatocyte apoptosis, promoting Th1 cell differentiation and NK T cell exhaustion.⁷⁸ Activation of NF-κB in macrophages causes pyroptosis, which recruits more macrophages secreting transforming growth factor beta 1 (TGF-β1) to activate HSCs and worsen liver fibrosis.⁷⁸ Activation of NF-κB and production of insulin growth factor binding protein 7 in macrophages also promotes insulin resistance.⁸⁴ Some macrophages, in addition to the M2 type classified previously, show an anti-inflammatory effect in MASLD. These cells express caspase 3 through activation of PPARδ to induce apoptosis of pro-inflammatory macrophages and secrete metalloproteinases MMP9/12 to degrade the extracellular matrix and slow fibrosis.⁷⁷^,⁸⁴ In addition to macrophages, neutrophils, eosinophils, and even platelets play important roles in inflammation in MASLD. Neutrophils contribute to the development of MASH and even malignant transformation by secreting neutrophil extracellular traps (NETs).⁸⁵ In patients with MASH, NETs are significantly elevated in the liver, which may be driven by complement component C3-mediated activation of neutrophil gene expression.⁸⁶ Although NETs do not directly kill hepatocytes, they activate macrophages and modulate T cell functions. Furthermore, NETs accelerate clotting by shortening coagulation time and promoting fibrin formation; thereby, exacerbating the pro-inflammatory hepatic microenvironment.⁸⁷ Neutrophils also associate with macrophages via miR-233 to regulate liver fibrosis.¹⁶^,⁸⁸ Furthermore, eosinophils may have a pro-inflammatory effect by secreting IL-13.⁷² Activated platelets facilitate the activation of NLRP3 inflammasome, increasing IL-1β production in neutrophils and macrophages and exacerbating the inflammatory response.¹⁶^,⁷²

The third stage in progression to fibrosis is inflammatory liver destruction by lymphocytes. Pro-inflammatory factors, damage-associated molecular patterns (DAMPs), and pathogen-associated molecular patterns produced by hepatocytes, macrophages, and HSCs recruit and activate lymphocytes, causing the release of inflammatory factors and promoting fibrosis progression.⁷² B cells that promote MASLD,89, 90, 91 cytokines, such as B cell activating factor, oxidative stress-specific epitopes, and myeloid differentiation factor 88, activate B cells in the liver by a T cell-independent mechanism.⁹² Activated B cells promote T cell activation through antigen presentation via elevated major histocompatibility complex class I/II and costimulatory CD86 expression. IL-6 and TNFα secretion further stimulates T cells, macrophages, and HSCs.⁷²^,⁸⁹ Additionally, immunoglobulin G from plasma cells exacerbates lobular inflammation and hepatocyte damage (evidenced by transaminase elevation), while immunoglobulin A drives macrophage activation through Fcα receptor-mediated signaling.⁹²^,⁹³ Moreover, macrophages, DCs, and B cells can activate T cells in the liver as antigen-presenting cells to ameliorate MASLD. Different subsets of T cells have the opposite effect on MASLD progression.⁹⁴ Th1 cells secrete interferon-gamma, and Th17 cells secrete IL-17, which synergistically promote liver fibrosis. Th2 cells can produce IL-4, IL-5, and IL-13, which usually play an anti-inflammatory role, while Th22 and regulatory T cells may have both anti-fibrotic and pro-fibrotic effects.⁹⁴^,⁹⁵ Notably, the loss of CD4⁺ T cells during the development of MASLD is strongly associated with hepatocellular carcinoma.⁹⁶ Activated by IL-15, liver-resident CXCR6⁺ CD8⁺ T cells kill hepatocytes by secreting TNF and expressing Fas ligand, leading to liver injury.⁹⁷ Under sustained inflammatory and injury signaling, HSCs undergo metabolic reprogramming driven by activation of TGF-β and the PPARβ/δ pathway. This transition promotes a myofibroblast-like process characterized by enhanced glycolysis, lipid droplet mobilization and increased β-oxidation, glutamine catabolism, and ER stress via IRE1α-XBP1 axis activation.⁹⁸^,⁹⁹ These processes collectively drive HSC differentiation into alpha smooth muscle actin-positive myofibroblasts, which transcriptionally upregulate profibrotic genes (e.g., COL1A1, TIMP1). Consequently, excessive collagen deposition and inhibition of matrix metalloproteinase activity lead to pathological extracellular matrix accumulation and cross-linking, culminating in liver fibrosis.⁹⁸

Multiple hits trigger a sustained inflammatory cascade that drives disease progression toward advanced hepatic fibrosis. Lipotoxic substances, bacterial endotoxins, and pro-inflammatory cytokines activate resident immune cells, recruit lymphocytes, and perpetuate hepatocellular injury. This coordinated response induces architectural disruption of the liver parenchyma and promotes irreversible fibrotic remodeling through HSC activation. The efficacy of anti-inflammatory and anti-fibrotic agents, including galectin-3 inhibitors, CCR2/CCR5 antagonists, and anti-TNFα drugs, remains under validation in clinical trials. Conversely, therapeutic candidates, such as TLR4 antagonists, NLRP3 inhibitors, p53 activators, and anti-TGF-β antibodies, have demonstrated promising potential in preclinical animal models.⁵⁴

3. Donors with MASLD in liver transplantation

Liver transplantation is the most effective treatment to save the lives of patients with end-stage liver disease or hepatocellular carcinoma, but donor shortage, as one of the most critical challenges in liver transplantation, gravely limits transplantations.¹⁰⁰ Additionally, because MASLD affects a progressively expanding population, healthy donor livers are scarce, with steatosis is present in approximately 9%–26% of donor livers.¹⁰¹ Using extended criteria donor livers with MASLD for transplantation and expanding the donor pool will help alleviate donor liver insufficiency.¹⁰²

3.1. Current status of steatotic donor liver applications

Hepatic steatosis is often divided into microvesicular steatosis and macrovesicular steatosis, and the pathological type of MASLD is usually macrovesicular. Hepatic steatosis can be divided into three grades on the basis of the severity as mild (<30% of the liver involved), moderate (30%–60%), and severe (>60%).¹⁰³^,¹⁰⁴ Clinically, most donor livers with steatosis are not abandoned, and several studies have shown that steatotic donor livers and healthy livers show no significant difference regarding long-term patient survival and graft survival after transplantation.105, 106, 107, 108 However, some studies have suggested that the incidence of primary graft dysfunction (PGD) and primary non-function (PNF) after transplantation with steatotic donor livers is significantly higher than that with healthy livers, and a high degree of steatosis is an independent risk factor for adverse post-operative outcomes.¹⁰³^,¹⁰⁹ Studies indicate that donor livers with moderate steatosis carry a 1.53-fold higher risk of graft failure compared with normal livers. Moreover, moderate-to-severe hepatic steatosis is associated with approximately twice the risk of PNF.110, 111, 112 Notably, the degree of steatosis in the donor liver may regress after transplantation, and donor livers with moderate steatosis may still completely recover.¹⁰³^,¹¹³ Therefore, MASLD donor livers with mild steatosis or moderate steatosis in good general condition (i.e., healthy donor, donor younger than 55 years of age, cold ischemia time less than 8 h) can be used for transplantation.¹⁰⁵ In contrast, the safety of donor livers with severe steatosis is controversial. It may be possible to use these livers as a graft if a short cold ischemia time can be ensured and the recipient's condition is stable.¹¹⁴

3.2. Mechanism of steatotic donor liver injury after transplantation

PGD, PNF, and multiple post-operative complications, such as transfusion-related acute lung injury, systemic inflammatory response syndrome, disseminated intravascular coagulation, and acute kidney injury may be more likely if steatotic livers are used for transplantation and may be associated with ischemia-reperfusion injury (IRI) and cold ischemic injury.¹⁰²^,¹¹⁵

Steatotic donor livers have a higher risk of IRI, which is closely associated with long-term complications, such as PGD, PNF, graft injury, fibrosis, rejection, and biliary injury.¹¹⁶ IRI in the liver depends on cell injury during ischemia, activation of the inflammatory response during reperfusion, and microcirculatory disturbances.¹¹⁷ Pathological changes in the livers of patients with MASLD, such as fat accumulation, cell stress, and microenvironmental inflammatory status, may be responsible for the increased risk of IRI (Fig. 2).

Hypoxia may cause more serious damage to liver cells in patients with MASLD in the ischemic state (Fig. 2A). Hepatic lipid deposition leads to increased hepatocyte volume, which narrows liver sinusoids and damages the microcirculation. These changes lead to chronic hypoxia and low intracellular adenosine triphosphate (ATP) concentrations. In these conditions, hepatocytes in the fatty liver are more likely to experience ATP depletion during ischemia, resulting in sodium/potassium ATPase failure, intracellular ion abnormalities, and calcium overload, leading to cell death.¹⁰³^,¹¹⁷^,¹¹⁸ Additionally, in MASLD donor livers under hypoxic stress, ceramide accumulation within hepatocyte lipid droplets promotes the formation of mitochondria-associated ER membranes.¹¹⁹ This facilitates the transfer of lipotoxic metabolites to mitochondria, inducing mitochondrial permeability transition pore opening. Subsequent leakage of cytochrome c and calcium into the cytosol activates the UPR via IRE1α, PERK, and ATF6 pathways, as detailed in Section 2.5, culminating in ER stress. Calcium is released from the ER continuously, damaging mitochondria, leading to oxidative stress.⁶⁷^,¹¹⁸ Under hypoxia and stress, dysregulated activation of the UPR and excessive autophagy cooperatively drive hepatocyte death through both necrosis and apoptosis, dramatically worsening graft injury in MASLD donor livers.

Following revascularization, inflammatory reactions, and microcirculatory disturbances may be more severe in MASLD donor livers compared with healthy livers (Fig. 2B). Compared with the healthy liver, the production of and damage from ROS in MASLD livers are significantly higher.¹¹⁷^,¹²⁰ As stated, MASLD livers are inflammation-promoting because macrophages and neutrophils are recruited and activated. These cells secrete various pro-inflammatory factors, which induce damage and apoptosis of hepatocytes and other non-parenchymal cells.¹⁶^,⁷² Following reperfusion of the ischemic donor liver, oxygen content increases, and cellular respiration intensifies. This is combined with impaired mitochondrial oxidative respiratory chains in the hepatocytes of MASLD livers, which decreases DNA expression and activity of mitochondrial respiratory chain complexes I, III, IV, and V, and leads to increased ROS production.¹¹⁷^,¹²⁰ Excessive ROS concentrations initiate cell death. On the one hand, this leads to lipid peroxidation, attacking the protein and lipid in the cell membrane and mitochondrial membrane, exacerbating mitochondrial damage, and leading to cell necrosis.¹²⁰^,¹²¹ On the other hand, oxidative stress leads to the production of DAMPs, activating inflammatory cells, such as macrophages and neutrophils, through PPRs, exacerbating inflammation in MASLD and inducing apoptosis in the liver.¹¹⁷^,¹²² Kupffer cells and neutrophils play important roles in the inflammation that follows reperfusion in MASLD donor livers. Under the influence of ROS and aggregated palmitic acid, Kupffer cells suffer ER stress through the activation of the IRE1α pathway, promoting phenotypic changes in macrophages that increase their pro-inflammatory abilities.¹²² Similarly, NLRP3 expression levels were elevated in a murine ischemia-reperfusion model, leading to cytokine release and cellular pyroptosis by mediating inflammasome activation.¹²³ Pro-inflammatory factors, such as IL-17a intensify neutrophil infiltration and further exacerbate inflammatory responses.¹²¹ The degree of microcirculatory disturbance following reperfusion in MASLD donor livers is higher than that in normal grafts. This microcirculatory disturbance is associated with hemodynamic disturbances resulting from sinusoid stenosis and irregularities in the fatty liver, endothelial injury, and adhesion and aggregation of blood cells, such as macrophages and platelets.¹⁰³^,¹¹⁶

IRI can also lead to serious systemic complications. Following reperfusion injury in MASLD liver grafts, cell death and lysis may release numerous lipid droplets that enter the bloodstream, leading to fat embolism and serious transplant complications, such as transfusion-related acute lung injury, systemic inflammatory response syndrome, disseminated intravascular coagulation, and acute kidney injury.¹²⁴

Hypothermia and hypoxia during cold ischemia cause hepatocellular injury by damaging organelles, such as mitochondria, the ER, and lysosomes, and the damage is more severe in MASLD donor livers versus healthy donor livers.¹¹⁵ During cold ischemia, the activity of complexes I, II, and III in the mitochondrial respiratory chain decreases, lysosomal secretion and release increases, and ER stress increases in steatotic livers, which results in donor cold ischemia injury.¹¹⁵^,¹²⁵^,¹²⁶ Activation of adenosine monophosphate-activated protein kinase, aldehyde dehydrogenase 2, heme-oxygenase 1, and other related pathways can protect organelles and reduce ubiquitin-dependent degradation of unfolded proteins to reduce cold ischemic injury and prolong MASLD graft preservation.¹¹⁵^,127, 128, 129

The use of steatotic donor livers in transplantation significantly amplifies the risk of IRI, driving a cascade of adverse outcomes. Pathological hallmarks of MASLD, including chronic hypoxia, lipid droplet accumulation, mitochondrial dysfunction, and a pro-inflammatory microenvironment, predispose these grafts to cellular stress during ischemia and reperfusion. Reducing graft ischemia time and appropriate post-operative metabolic management are essential to optimize the use of MASLD donor livers.

4. Discussion

MASLD is the most common chronic liver disease,¹ and studies of the pathogenesis and treatment of MASLD are on-going. According to existing studies, susceptibility to MASLD is influenced by genetic, metabolic, and endocrine factors.¹⁶ Various SNPs and epigenetic modifications associated with glucose and lipid metabolism or liver fibrosis are closely related to the risk of developing MASLD. Various endocrine diseases, such as T2DM, growth hormone deficiency, and hypothyroidism are also risk factors for MASLD.48, 49, 50 The initial factor in the pathogenesis of MASLD is fat accumulation caused by lipid metabolism disorders. This process is associated with a high-fat and high-sugar diet, insulin resistance, and lipoprotein secretion and transport. This process is promoted by changes in the gut microbiota composition that change gut permeability and result in abnormal bile acid metabolism and bacterial product translocation. Following the accumulation of lipids, hepatocyte homeostasis is gradually destroyed, and lipotoxic substances synergize with stress factors, such as hyperlipidemia, inflammation, viruses, and drugs, to induce ER stress in hepatocytes. Chronic ER stress leads to mitochondrial membrane damage, ROS production and release, proteotoxicity production, and activation of apoptosis, ultimately leading to cell death. These changes in hepatocytes are detected by tissue-resident γδ T cells, MAIT cells, and DCs, which recruit and activate macrophages, neutrophils, and lymphocytes through inflammatory mediators, triggering the inflammatory cascade and activating HSCs, leading to liver fibrosis.

With research on the pathogenesis of MASLD, the relationship between multiple organs or tissues, such as the gastrointestinal tract, adipose tissue, and pancreas, and the development of MASLD has become increasingly apparent. Related molecular pathways have been continuously discovered, which promotes the understanding of MASLD and facilitates the development of treatments. As a disease associated with the metabolism of multiple organs and systems, the importance of multidisciplinary management in the treatment of MASLD is evident. Diet and health management combined with drug therapy targeting metabolic regulation, insulin sensitization, oxidative stress, immune regulation, anti-fibrosis therapy, and intestinal flora modification, have made it possible to reverse the progression of MASLD.¹³⁰

It is also necessary to study the pathogenesis and molecular changes in MASLD to reveal the mechanism of injury after liver transplantation with MASLD donor livers, which contributes to assessing the availability of MASLD donor livers and post-transplantation treatments. Donor livers with a high degree of steatosis may have an increased risk of adverse post-operative clinical outcomes.¹⁰² MASLD and IRI share key pathological mechanisms. In both conditions, hepatic microvascular perfusion is compromised: lipid accumulation in MASLD compresses sinusoids, while cold ischemia during transplantation induces endothelial dysfunction. This establishes a hypoxic microenvironment that drives hepatocyte injury. Intracellular accumulation of lipotoxic metabolites and ROS triggers ER stress and oxidative stress, disrupting cellular integrity and activating CHOP-mediated apoptosis. Concurrently, a pro-inflammatory state characterized by elevated IL-1β, TNF-α, and IL-6 recruits and activates macrophages, neutrophils, and lymphocytes, amplifying hepatic damage through sustained inflammation. In MASLD donor liver transplantation, narrow sinusoids worsen hypoxia during vascular occlusion. Lipotoxicity, inflammatory mediators, and massive ROS generation during reperfusion synergistically amplify ER stress and oxidative stress. The baseline pro-inflammatory microenvironment in MASLD livers, characterized by pre-activated Kupffer cells and leukocyte infiltration, potentiates a heightened and accelerated post-reperfusion inflammatory response. Collectively, these mechanisms increase graft vulnerability to IRI and cold ischemic injury, increasing the risks of PGD and PNF, as well as a variety of post-operative complications. However, the degree of steatosis in some donor livers regresses after transplantation, which may be related to dietary management, intestinal microenvironmental changes, and hepatic inflammation inhibition by immunosuppressants. Therefore, several studies have shown that livers with mild or moderate steatosis can be used as grafts and those with severe steatosis should be used only in select recipients with stable conditions and without metabolic disorders.

Current therapeutic strategies for MASLD donor liver transplantation focus on graft pre-conditioning and preservation. A 15-min ischemic pre-conditioning period can mitigate injury in steatotic grafts by inducing protective autophagy.¹³¹ Compared with conventional static cold storage, preservation strategies that shorten ischemia duration and alleviate hypoxia demonstrate superior graft survival outcomes. Since its implementation in 2017, ischemia-free transplantation has proven effective in improving the function of steatotic donor livers.¹³² Both normothermic and hypothermic oxygenated machine perfusion significantly reduce the incidence of early allograft dysfunction and result in fewer post-operative complications, such as biliary injury.¹¹² According to Chinese expert consensus on organ protection in transplantation, cold ischemia time should be limited to <8 h. For MASLD donor livers, this threshold requires further reduction to 6 h to mitigate cold ischemia-related graft injury. Adjunctive strategies, such as ischemia-free liver transplantation and hypothermic oxygenated machine perfusion are critical to enhance organ preservation in such high-risk grafts.

An often overlooked fact is that the post-transplantation management of MASLD grafts is more important than that for normal donor grafts. In MASLD, lifestyle modification and immunosuppressant, hepatoprotective, metabolism-regulating, and oxidative stress therapy, are the cornerstones following liver transplantation. Given that immunosuppressive agents, such as glucocorticoids and tacrolimus are inducers of hepatic steatosis, and mammalian target of rapamycin inhibitors demonstrate partial efficacy in mitigating obesity,¹³³^,¹³⁴ immunosuppressive regimens following MASLD donor liver transplantation require judicious selection and monitoring. Targeted therapeutics for MASLD should be applied post-transplantation. Agents with proven efficacy in Phase Ⅲ and Ⅳ trials, including thyroid hormone receptor beta agonists, PPARγ agonists, glucagon-like peptide 1-receptor agonists, sodium-glucose cotransporter-2 inhibitors, and FXR agonists, may offer protective benefits in MASLD donor liver transplantation.

The mechanism of MASLD donor liver damage is closely related to the pathogenesis of MASLD, which permits overlap in therapeutic management. MASLD is a disease associated with multiple organs and systems, which makes multidisciplinary management and comprehensive treatment particularly important. Although various novel metabolic drugs have been developed and permitted for use in clinical trials, there is still no means of completely reversing the progression of MASLD. An in-depth understanding of the pathogenesis of MASLD and MASLD-associated graft damage may provide information on therapeutic targets and the development of systematic and personalized treatment plans for patients with MASLD and those who undergo MASLD donor liver transplantation.

5. Conclusion

This review provided an in-depth discussion of the pathogenesis of MASLD. The development of MASLD is closely related to genetics, lipid metabolism disorders, endocrine disorders, intestinal flora imbalances, abnormal hepatocyte homeostasis, and hepatic inflammation. These pathological changes in MASLD donor livers worsen injury during IRI that destroy graft function and structure. Understanding the pathogenesis is conducive to filling the gap in treatment methods for MASLD and providing a new direction for targeted therapy. Additionally, awareness of the mechanism of MASLD donor liver damage will help improve the strategy for MASLD donor liver use and protect transplanted grafts.

CRediT authorship contribution statement

Chuheng Gou: Writing – original draft, Investigation, Formal analysis, Data curation. Wenjie Zhang: Writing – review & editing, Visualization, Methodology. Hao Xu: Writing – review & editing, Resources. Hong Zhang: Investigation. Rui Ding: Supervision, Funding acquisition. Xuan Zhang: Writing – review & editing, Project administration, Funding acquisition, Conceptualization.

Informed consent

Not applicable.

Organ donation

Not applicable.

Ethics statement

Not applicable.

Data availability statement

No new data were created or analyzed in this study. Data sharing does not apply to this article.

Animal treatment

Not applicable.

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work the authors did not use generative AI or AI -assisted technologies.

Funding

This research was funded by the National Natural Science Foundation of China, grant number 82070681, Talent Promotion program of the Fourth Military Medical University, grant number 2023RCJB10, and the Innovative Medical Research Program of Xijing Hospital, grant number XJZT24CY13. The article processing charge was funded by Xijing Hospital.

Declaration of competing interest

The authors and funders declare no conflicts of interest.

Acknowledgments

The authors extend sincere appreciation to all members of our research group for their invaluable contributions to manuscript preparation and proofreading. We are grateful to Yuwei Xie for guidance in figure preparation and visualization design.

Contributor Information

Chuheng Gou, Email: 2475474679@qq.com.

Wenjie Zhang, Email: zhangjlk1002@163.com.

Hao Xu, Email: haux2014@163.com.

Hong Zhang, Email: ahrhong@126.com.

Rui Ding, Email: hepatomd@163.com.

Xuan Zhang, Email: zhangxuantj@163.com.

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Associated Data

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Data Availability Statement

No new data were created or analyzed in this study. Data sharing does not apply to this article.

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PERMALINK

Pathogenesis of metabolic dysfunction-associated steatotic liver disease and donor liver damage

Chuheng Gou

Wenjie Zhang

Hao Xu

Hong Zhang

Rui Ding

Xuan Zhang

Abstract

1. Introduction

2. Pathogenesis of MASLD

2.1. Genetics

Fig. 1.

2.2. Lipid metabolism disorders

2.3. Endocrine disorders

2.4. Intestinal flora imbalances

2.5. Disrupted hepatocyte homeostasis

2.6. Hepatic inflammation and fibrosis

3. Donors with MASLD in liver transplantation

3.1. Current status of steatotic donor liver applications

3.2. Mechanism of steatotic donor liver injury after transplantation

Fig. 2.

4. Discussion

5. Conclusion

CRediT authorship contribution statement

Informed consent

Organ donation

Ethics statement

Data availability statement

Animal treatment

Declaration of generative AI and AI-assisted technologies in the writing process

Funding

Declaration of competing interest

Acknowledgments

Contributor Information

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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