MASLD in children: integrating epidemiological trends with mechanistic and translational advances

Metabolic dysfunction–associated steatotic liver disease (MASLD) is the most common pediatric liver disease, affecting approximately 10% of children. Its prevalence is rising at an alarming rate, with cases increasingly identified even in early childhood. While MASLD shares key features across the lifespan, its earlier onset reflects developmental vulnerabilities and unique mechanistic drivers. Perinatal influences, including maternal obesity, gestational diabetes, and early-life nutritional exposures, play a central role by disrupting metabolic programming, driving mitochondrial dysfunction, and inducing epigenetic modifications. These early stressors interact with genetic predispositions, such as PNPLA3 and TM6SF2 variants, to amplify susceptibility and shape disease severity. Pediatric MASLD also exhibits distinct histological features, particularly predominant periportal (zone 1) steatosis, inflammation, and fibrosis, which contrast with the centrilobular or pericentral (zone 3) patterns often seen in adults. These findings provide insight into spatial heterogeneity, developmental pathophysiology, and unique disease progression trajectories in children. Addressing MASLD in children requires pediatric-specific approaches to diagnosis, risk stratification, and intervention. By integrating epidemiological trends, mechanistic insights, and translational advances, this Review highlights opportunities for targeted therapies and prevention strategies aimed at mitigating early-life drivers of MASLD, reducing disease burden, and improving long-term outcomes.

The rising prevalence of MASLD in children, alongside its unique clinical presentation, highlights the need to understand its epidemiological trends. Variations in prevalence by age, sex, and ethnicity provide critical insights for identifying at-risk populations and tailoring preventive strategies. This section explores these trends, laying the foundation for understanding the clinical and biological mechanisms driving pediatric MASLD.

Age. MASLD prevalence increases with age throughout childhood and adolescence. The Study of Child and Adolescent Liver Epidemiology (SCALE), which analyzed liver histology of children aged 2–19 years undergoing autopsy in San Diego County (1993–2003), found an overall MASLD prevalence of 9.6%, with notable age-specific variations: 0.7% in children aged 2–4 years, 3.3% in those aged 5–9 years, 11.3% in children aged 10–14 years, and 17.3% in adolescents aged 15–19 years (3). Complementing these findings, a systematic review and meta-analysis of international studies estimated a 7.6% MASLD prevalence in the general pediatric population (6).

Although MASLD is most commonly diagnosed during the peripubertal period, evidence suggests hepatic steatosis is increasingly prevalent in younger children. The Viva La Familia study, using elevated ALT as a surrogate marker, identified suspected MASLD in 15% of children aged 4–5 years, 21% in those aged 6–11 years, and 30% in adolescents aged 12–19 years (7). Additional evidence, including a Canadian review of CT scans and an Israeli study of children with obesity, highlights the early onset of MASLD. Notably, children under 6 years of age are increasingly affected, often presenting with elevated ALT levels and increased adiposity (8, 9).

Sex. Sex-based differences in MASLD prevalence are well-documented; with respect to biological sex, male individuals consistently exhibit higher rates than female individuals across all pediatric age groups. From here on, we will use the terms “males” and “females” to refer to humans. In the general pediatric population, approximately 11% of males are affected compared with 7% of females, with this disparity becoming more pronounced during adolescence. This difference is partly attributed to fat distribution patterns, as males tend to accumulate more visceral fat — a key risk factor for hepatic steatosis — whereas females typically have higher levels of subcutaneous fat, which is less strongly associated with MASLD (10). Puberty further amplifies these differences, likely due to hormonal influences on adipose tissue distribution and metabolic regulation. Among children with obesity, MRI proton density fat fraction studies show that MASLD affects 29% of males versus 22% of females (5).

Race and ethnicity. The risk of MASLD varies significantly across racial and ethnic groups, reflecting a complex interplay of genetic, environmental, and cultural factors. Findings from the Child and Adolescent Trial for Cardiovascular Health (CATCH) indicate that Hispanic adolescents with obesity are more likely to present with elevated ALT levels compared with their White peers, whereas Black adolescents with obesity are less likely to do so (11). Data from the SCALE study revealed substantial disparities, with Hispanic children and adolescents exhibiting the highest prevalence of hepatic steatosis (11.8%) and Black children the lowest (1.5%). Asian children demonstrated a prevalence of 10.2%, while White children had a prevalence of 8.6% (3). Analysis of National Health and Nutrition Examination Survey (NHANES) data from 2011 to 2018 by Mischel et al. further highlighted these disparities. Among adolescents, the overall prevalence of elevated ALT, a surrogate marker for MASLD, was 16.5%, rising to 39.5% among those with obesity (4).

Stratified by ethnicity, Asian American adolescents emerged as a particularly high-risk group. Notably, among adolescents with BMI in the overweight range, Asian individuals had a higher prevalence of elevated ALT (27.0%) compared with their White (12.8%) and Black (8.4%) counterparts, suggesting increased susceptibility to MASLD at lower BMI thresholds. Supporting these findings, Lee et al. demonstrated that Asian subgroups also exhibit significant heterogeneity in MASLD risk (12). For example, Filipino, Chinese, and Southeast Asian males had 1.7- to 2.1-fold higher odds of elevated ALT compared with White males, while Filipina and Chinese females with obesity demonstrated more than twofold higher odds of ALT elevation. Similar subgroup heterogeneity may also exist within Hispanic populations. While MASLD is highly prevalent among Hispanic children, current studies group individuals with diverse ancestral backgrounds together, which may obscure important differences in disease risk. For example, individuals of Indigenous Mexican or Central American ancestry may have a different genetic and metabolic predisposition to MASLD compared with those of predominantly European ancestry. However, pediatric data specifically addressing these differences remain limited.

Social determinants of health. Emerging data suggest that food insecurity and other socioeconomic barriers contribute to disparities in MASLD prevalence and severity. At Cincinnati Children’s Hospital, one-third of children with MASLD reported at least one unmet social need, with 13% of children experiencing food insecurity and 10% experiencing transportation barriers (13). Studies have linked food insecurity in childhood to a 3- to 4-fold increased risk of MASLD, highlighting the role of socioeconomic status in disease susceptibility (14). Additionally, a national survey of pediatric gastroenterologists identified multiple barriers to MASLD care, including limited access to dietitians, lack of insurance coverage for dietary counseling, and economic constraints affecting families’ ability to implement lifestyle recommendations (15). Notably, nearly one in three pediatric gastroenterologists reported encountering at least three substantial barriers when managing pediatric MASLD. Social challenges, such as food deserts, family financial instability, and limited access to physical activity resources, may further hinder effective intervention strategies.

Variations in MASLD across age, sex, race, ethnicity, and socioeconomic status reflect the complex interplay of biological and environmental factors in shaping disease risk. While genetic susceptibility and metabolic programming contribute to these differences, growing evidence suggests that early-life exposures, including maternal health, in utero exposures, and childhood nutrition, further shape long-term disease trajectories. These early-life factors offer essential insights into the unique manifestations of pediatric MASLD and pave the way for exploring its developmental origins.

The observed trends in MASLD prevalence across age, sex, and racial or ethnic groups point to early-life factors as key determinants of disease susceptibility (Figure 1). Perinatal influences — including maternal health, in utero exposures, and early postnatal conditions — play a central role in programming metabolic pathways that contribute to MASLD. These factors provide a foundation for understanding the developmental origins of MASLD and offer critical insights into its distinct manifestations in children. The reviewed preclinical studies herein provide insight into pediatric MASLD pathogenesis, potential biomarkers, and therapeutic targets; it is important to note that human application requires further validation in well-designed clinical trials

Figure 1

Perinatal and early-life factors contributing to MASLD development in children and potential therapeutic interventions. Maternal risk factors such as an unhealthy diet, obesity, gestational diabetes, and placental dysfunction lead to mitochondrial dysfunction, increased reactive oxygen species production, epigenetic modifications, immune dysregulation, dysbiosis, and metabolic reprogramming in the offspring, all of which promote MASLD onset. Intervention strategies focus primarily on lifestyle modifications during pregnancy and postnatally, including maternal adherence to a Mediterranean diet, physical exercise, breastfeeding, and judicious use of antibiotics in the child.

Maternal obesity, gestational diabetes, and birth weight. Maternal metabolic health during pregnancy exerts a lasting influence on offspring, making obesity and gestational diabetes two of the most well-established perinatal risk factors for MASLD in children (16). These conditions disrupt maternal-fetal nutrient homeostasis, creating a proinflammatory and lipotoxic intrauterine environment. Such exposures can alter fetal metabolic programming, emphasizing the need for maternal health optimization and early nutritional interventions (16).

Birth weight further modulates MASLD risk, with both low birth weight (LBW) and high birth weight (HBW) being associated with increased disease susceptibility (17, 18). A study by Newton et al. involving 538 children with MASLD demonstrated that HBW was linked to significantly higher odds of severe steatosis (odds ratio [OR], 1.82) and metabolic dysfunction–associated steatohepatitis (MASH) (OR, 2.03) compared with normal birth weight. Conversely, LBW was associated with markedly increased odds of advanced fibrosis (OR, 2.23) (19). The Early Vascular Ageing in the YOUth (EVA4YOU) project further identified rapid postnatal weight gain, particularly in preterm infants, as a critical amplifier of MASLD risk (20). Breij et al. extended these findings, linking accelerated weight gain during the first three postnatal months in preterm-born individuals to a heightened risk of early adulthood MASLD (21).

In utero programming and the fetal liver. The origins of MASLD can be traced back to in utero metabolic programming driven by maternal nutrition and intrauterine environment (22, 23). The fetal liver is particularly vulnerable to metabolic dysregulation and lipotoxic injury due to developmental limitations. First, fetal adipose depots, crucial for buffering excess transplacental lipids in maternal obesity, mature late in gestation. Second, compared with the adult liver, fetal hepatocytes have fewer mitochondria, lower carnitine palmitoyl-CoA transferase-1 (CPT1) activity, and reduced gluconeogenic capacity (24). These physiological constraints, combined with excess nutrient supply, disrupt fatty acid flux and promote accumulation of lipotoxic metabolites such as diacylglycerols and ceramides. Wesolowski et al. reported elevated hepatic ceramide levels in nonhuman primate fetuses of mothers with obesity and a Western diet, persisting even after maternal dietary improvements during pregnancy, supporting a lasting effect of maternal diet on fetal liver metabolism (25). These toxic intermediates intensify hepatocyte injury and inflammation, establishing a foundation for MASLD development (26, 27).

Nonhuman primate models provide valuable insights into the fetal origins of MASLD. Exposure to a maternal high-fat diet (HFD) during gestation significantly increased fetal hepatic triglyceride accumulation, oxidative stress, and the hepatic expression of gluconeogenic enzymes and transcription factors (28). Early-life exposure to maternal insulin resistance further exacerbated these effects by upregulating the hepatic expression of proinflammatory and de novo lipogenic genes. Notably, these gene expression changes persisted postnatally, even after weaning to a normal diet, priming the offspring for the development of MASLD (29). Human studies have confirmed the maternal precursors of pediatric MASLD, linking maternal lipid concentrations, especially in early pregnancy, to higher offspring hepatic fat content (30).

Placental dysfunction and fetal hypoxia. Placental dysfunction and fetal hypoxia are also drivers of MASLD pathogenesis. For example, in Sprague-Dawley rats, fetal exposure to maternal hypoxia led to the postnatal development of a more severe MASLD phenotype in offspring fed an HFD during adulthood. Molecular studies revealed significant alterations in insulin-signaling and adipogenic pathways in these offspring, including downregulation of insulin receptor substrate 2 (IRS2) and upregulation of adipogenic signaling mediators such as sterol-regulatory element-binding protein-1 (SREBP1) and fatty acid synthase (31). Nonetheless, nonhuman primate studies indicate that placental contributions to MASLD programming extend beyond the impact of hypoxia, as Western diet alters placental and fetal liver microRNA expression and the maternal microbiome (32). Moreover, maternal obesity and HFDs induce placental inflammation via increased cytokine expression and activation of mitogen-activated protein kinases and early growth response protein-1 pathways (33). Furthermore, in a mouse model, maternal obesity is linked to increased expression of placental fatty acid transport protein 6 and fatty acid binding protein 3, which enhance lipid transport to the fetus and result in fetal liver steatosis (34). Emerging evidence suggests that extracellular vesicles released by the placenta can influence fetal development and metabolism. These vesicles carry bioactive molecules, such as proteins, lipids, and miRNAs, which can modulate fetal tissue function and contribute to the programming of metabolic diseases (35).

Epigenetics and fetal programming. Umbilical cord–derived mesenchymal stem cells from offspring of mothers with obesity exhibit programmed metabolic differences linked to increased infant adiposity. Baker et al. reported disruptions in the glutathione cycle, incomplete β-oxidation, and altered gene expression patterns — including upregulated membrane lipid transport, mitochondrial oxidative phosphorylation, and electron transport chain components, along with downregulated mitochondrial biogenesis and insulin-dependent energy-sensing pathways (36, 37). These findings are particularly relevant because mesenchymal stem cells may serve as progenitors of hepatic stellate cells (HSCs), whose metabolic alterations contribute significantly to fibrosis progression (38).

Human studies reinforce the effect of maternal adiposity and insulin resistance on offspring metabolism. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study demonstrated associations between maternal BMI and neonates’ cord blood levels of branched-chain amino acids and their metabolic by-products (39). Moreover, maternal glucose tolerance was linked to increased cord blood levels of ketone 3-hydroxybutyrate, its carnitine ester, glycerol, and a medium-chain carnitine ester. Such metabolites promote hepatic dysfunction, mitochondrial impairment, and insulin resistance, emphasizing their role in predisposing offspring to MASLD.

Children exposed in utero to a “thrifty phenotype” resulting from maternal undernutrition or placental insufficiency face heightened risks of metabolic disease when encountering nutrient-rich postnatal environments (40). Gene-protein enrichment analyses and protein interaction networks reveal that fetal adaptations to both maternal undernutrition and overnutrition result in significant alterations to gene expression, driven by differential epigenetic modifications. The maternal obesogenic environment promotes metabolic reprogramming of glucose and lipid metabolism, conferring an elevated risk of metabolic syndrome and hepatic steatosis in offspring (41).

Preclinical studies corroborate these findings, with mouse models showing that maternal overnutrition-induced hepatic DNA methylation contributes to more severe MASH with liver fibrosis in offspring (42). Similarly, nonhuman primate models have demonstrated that maternal HFD exposure leads to increased fetal liver H3K14 histone acetylation and reduced activity of the energy sensor SIRT1, a transcriptional effector crucial to lipid metabolism (43). In pediatric studies, epigenetic changes have been directly linked to MASLD. Increased blood DNA methylation at the HIF3A locus was observed in children with obesity and elevated ALT levels, independent of BMI. These findings suggest that oxidative stress response–related epigenetic modifications may predispose children to MASLD (44). Collectively, these studies support a role for epigenetic modifications induced by in utero exposure in the early development of severe MASLD. Interestingly, plasma miRNAs were associated with MASLD features in adolescents with severe obesity, showing the potential use of miRNA as disease biomarker (45).

Microbiome and postnatal dysbiosis. Maternal obesity has also been strongly linked to dysbiosis in offspring, further increasing susceptibility to MASLD. The development of the microbiome and the nascent immune system in early life plays a critical role in the pathogenesis of MASLD in children through mechanisms involving gut dysbiosis, immune dysregulation, and metabolic alterations (46, 47). Experiments involving fecal transplants from human newborns of obese mothers into germ-free mice revealed significant metabolic and inflammatory changes in the recipients. These mice exhibited increased hepatic expression of endoplasmic reticulum stress markers, proinflammatory cytokines, and periportal inflammation. Additionally, they showed impaired macrophage phagocytosis, reduced cytokine production, and accelerated weight gain. When exposed to an obesity-inducing diet, these colonized mice developed MASLD at an accelerated rate (48).

Endocrine-disrupting chemicals. Early-life exposure to endocrine-disrupting chemicals, known to disrupt endocrine and metabolic functions, is increasingly recognized in MASLD pathogenesis (49, 50). In utero or neonatal exposure to bisphenol A, widely used in polycarbonate plastics, has been associated with increased body weight and altered epigenetic programming during early stem cell development (51). Similarly, low-level exposure to environmental pollutants such as vinyl chloride induces persistent mitochondrial dysfunction linked to MASLD (49).

Maternal obesity, diet, and metabolic status shape pediatric MASLD risk through mechanisms, including mitochondrial dysfunction, reactive oxygen species generation, metabolic reprogramming, dysbiosis, and epigenetic alterations. Genetic variants that affect lipid metabolism, mitochondrial function, and fibrogenesis can amplify these early-life insults, further shaping the trajectory of MASLD. These risks are compounded by maternal HFD consumption during lactation and continued postweaning exposure to obesogenic diets (Figure 1). Future research is needed to elucidate how maternal health and diet during pregnancy affect fetal liver development and predispose children to MASLD, emphasizing mechanisms by which maternal nutrition and metabolic status program fetal liver metabolism and bile acid homeostasis (52).

The genetic landscape of MASLD, including both common variants and rare monogenic mutations, is explored in the next section, offering insight into how inherited and environmental factors converge to influence disease development.

While perinatal influences lay the foundation for MASLD risk, genetic predispositions further shape its onset and progression, particularly through interactions with early-life environmental factors. This section examines both common genetic variants and rare monogenic mutations that contribute to pediatric MASLD, emphasizing their functional roles, ethnic variability, and potential implications for clinical practice.

Genetic risk variants. Numerous single nucleotide polymorphisms (SNPs) influence pediatric MASLD onset and progression. Among these, the most extensively studied is PNPLA3 (encoding patatin-like phospholipase domain-containing 3), particularly the rs738409 polymorphism. This variant strongly associates with increased hepatic triglycerides; allele frequencies were reported to vary by ethnicity (53–58), with frequencies of approximately 0.49 in Asian populations (54), 0.48 among Hispanic children, 0.324 in White children, and 0.183 in African American children (53).

Variants in TM6SF2 (encoding transmembrane 6 superfamily member 2) and GCKR (encoding glucokinase regulatory protein) also play critical roles in MASLD pathogenesis. The TM6SF2 rs58542926 variant is associated with increased hepatic fat accumulation and reduced export of very low-density lipoprotein, potentially offering some protection against cardiovascular risk while being associated with higher prevalence of fibrosis and a higher NAFLD activity score (59). Meanwhile, the GCKR rs1260326 variant enhances de novo lipogenesis and liver inflammation (60). Di Costanzo et al. developed a weighted genetic risk score combining PNPLA3, TM6SF2, and GCKR risk alleles, conferring an eightfold higher risk of MASLD in Italian children with obesity (61).

While many MASLD-associated SNPs affect lipid metabolism, some directly impact mitochondrial function, emphasizing their role in disease progression (62). These genetic factors amplify MASLD risk when combined with perinatal or postnatal mitochondrial dysfunction, accelerating disease severity. The SAMM50 gene, encoding a mitochondrial membrane transporter critical for cristae structure and respiratory chain complex assembly, is linked to increased MASLD risk in Asian children (54). Homozygous variants of SAMM50 (rs2073080 and rs3761472), along with polymorphisms in PNPLA3 and TM6SF2, significantly increase the likelihood and severity of MASLD in this population.

A multicenter, family trio study in the United States further highlighted genetic determinants of pediatric MASLD. Goyal et al. genotyped 822 children with biopsy-proven MASLD and their parents across 60 candidate SNPs (58). Among these, PNPLA3 rs738409 emerged as the strongest genetic determinant of MASLD, correlating with steatosis, inflammation, and zone 1 pediatric MASH. The study also identified SNPs linked to specific histologic features, such as steatosis grade (PNPLA3 rs738409, TM6SF2, GCKR, and MTTP) and fibrosis stage (PARVB rs6006473, NR1I2, ADIPOR2, and OXTR). Notably, PARVB rs6006473 demonstrated a strong association with fibrosis severity.

Conversely, protective genetic factors have also been identified. The HSD17B13 rs72613567:TA variant, the first known protective polymorphism in MASLD, reduces the risk of progression from steatosis to steatohepatitis in both adults (63) and children (64). In a cohort of 685 children with obesity, carriers of this variant exhibited lower hepatic steatosis, serum transaminase levels, and fibrosis index scores (64). Although genetic predispositions to MASLD often overlap with obesity, variants such as TM6SF2 and HSD17B13 influence MASLD independently of obesity. In addition, PNPLA3 has been associated with MASH even in the absence of obesity (65), highlighting the complex interplay between genetic predisposition and metabolic factors.

Although these genetic variants provide valuable insights for risk stratification and prognosis, their clinical application in pediatric MASLD has not been established. Further research is needed to integrate these genetic markers into tailored nutritional interventions, clinical trial selection, and screening for complications such as portal hypertension and hepatocellular carcinoma.

Monogenic causes of obesity. Monogenic mutations in the leptin-melanocortin pathway are associated with early-onset severe obesity and metabolic complications, including MASLD. Key genes implicated are LEP (encoding leptin), LEPR (leptin receptor), POMC (proopiomelanocortin), and PCSK1 (proprotein convertase subtilisin/kexin type 1) (66). Targeted therapies, such as setmelanotide, a melanocortin-4 receptor (MC4R) agonist, have shown efficacy in treating obesity due to deficiencies in POMC, LEPR, and PCSK1, promoting weight loss and improving metabolic syndrome, including hepatic steatosis reduction (67). Additionally, in a phase 2 open-label trial, setmelanotide demonstrated promise for hypothalamic obesity, a condition often leading to severe, rapidly progressing MASH requiring liver transplantation in adolescence or young adulthood, with a high risk of recurrence in the graft (68–70). Furthermore, recombinant leptin analogs have improved the metabolic outcomes and reduced hepatic steatosis in patients with leptin deficiency and severe lipodystrophy (71, 72). These targeted therapies, combined with lifestyle modifications, offer a novel and effective approach to mitigating MASLD progression in monogenic and potentially in acquired hypothalamic obesity.

MASLD’s unique presentation in children is closely tied to hepatic zonation, with spatial and functional liver organization offering key insights into disease mechanisms. As a tissue-level disease, MASLD is characterized by steatosis with varying degrees of ballooning, inflammation, and fibrosis, all of which strongly influence prognosis. Schwimmer et al. first identified distinct pediatric steatohepatitis patterns, distinguishing cases from adults (73). Specifically, they described 2 distinct forms of steatohepatitis in children: one marked by ballooning degeneration with zone 3 perisinusoidal fibrosis, and another characterized by zone 1 portal inflammation and fibrosis (Figure 2). Building on this, Africa et al. compared children with exclusive periportal (zone 1) versus pericentral (zone 3) steatosis (74). Their findings revealed that zone 1 steatosis was associated with younger age and greater risk of advanced fibrosis, whereas zone 3 steatosis carried a higher likelihood of steatohepatitis. Data from the CyNCH clinical trial investigating cysteamine bitartrate delayed release (CBDR) in pediatric NAFLD further demonstrated that children with zone 1–based steatohepatitis responded significantly better to CBDR treatment than those with zone 3–based steatohepatitis (75). These findings show the importance of steatosis zonality in understanding the pathophysiology, natural history, and therapeutic responses. Fully understanding its implications will require deeper investigation into the metabolic, transcriptional, and immunological differences between zone 1 and zone 3 hepatocytes (Figure 2).

Figure 2

Patterns of steatosis distribution in pediatric MASLD. Hepatocytes are subject to distinct microenvironments by zone. Hepatocytes in zone 1 experience high levels of nutrients and gut microbial products, resulting in enhanced β-oxidation, gluconeogenesis, and other metabolic functions. In contrast, hepatocytes in zone 3 are exposed to relative hypoxia and elevated Wnt signaling, driving distinct signaling pathways and metabolic activities such as bile acid production and glutamine synthesis. These distinct microenvironments underpin the spatial heterogeneity of liver metabolism and pathology. (A) A periportal (zone 1) pattern of steatosis distribution with focal periportal expansion is more common in pediatric MASLD. The hepatocytes surrounding the portal tract (PT) show lipid droplet accumulation, whereas hepatocytes adjacent to the central vein (CV) are spared, with no lipid accumulation or perivenular fibrosis. (B) A perivenular (zone 3) pattern of steatosis distribution is more common in adult MASLD. Hepatocytes around the central vein contain prominent lipid droplets, whereas periportal hepatocytes (zone 1) surrounding the portal tract are spared from steatosis accumulation.

Severity of pediatric MASLD. Data from both community-based and clinical referral cohorts indicate significant variability in MASLD severity among children. In the SCALE study, approximately one-fourth of children with hepatic steatosis had steatohepatitis, providing an estimate of MASLD severity in the general pediatric population (3). In contrast, referral-based studies report that up to 50% of children with biopsy-confirmed MASLD have MASH, with periportal (zone 1) steatohepatitis being more common than pericentral (zone 3) steatohepatitis (76). Additionally, across large multicenter biopsy-based cohorts in the United States. and Europe, 20%–25% of children with MASLD have clinically significant fibrosis (stage 2 or higher) (77, 78). These differences likely reflect selection biases, as children who undergo liver biopsy are typically those with more severe disease or higher clinical concern for progression.

Microenvironment variations across the lobule. The liver lobule, the basic anatomical and functional unit of the liver, spans just 1–2 mm but exhibits profound microenvironmental differences across its zones. Blood enters via the portal vein and hepatic artery and exits through the central vein, creating distinct metabolic and signaling environments for hepatocytes in zone 1 (periportal) and zone 3 (pericentral), as first described by Rappaport et al. in the 1950s (79).

The blood entering the lobule is enriched with oxygen from the hepatic artery, along with nutrients, gut microbiome–derived products, and pancreatic hormones delivered via the portal vein. As it flows through the lobule, hepatocytes actively filter toxins and secrete metabolites and proteins, reshaping its composition. This process maintains systemic homeostasis: during feeding, hepatocytes absorb glucose to prevent hyperglycemia, while during fasting, they produce glucose to prevent hypoglycemia. Within the liver, this process establishes distinct hormonal and metabolic environments, with zone 3 hepatocytes near the central vein differing from those in zone 1 near the portal vein. Zone 3 cells experience relative hypoxia (80, 81) and an elevated insulin/glucagon ratio and likely reduced exposure to gut-derived metabolites (82).

Liver sinusoidal endothelial cells (LSECs) regulate hepatocyte zonation by secreting Wnt ligands, signaling molecules also involved in cancer and development. Zone 3 LSECs produce high levels of Wnts, exposing nearby hepatocytes to strong Wnt signaling, while zone 1 hepatocytes experience minimal exposure (83). Wnt ligands bind to specific receptors, stabilizing the transcriptional regulator β-catenin, which accumulates in the nucleus and directs gene transcription (84). Disrupting Wnt secretion from endothelial cells significantly impairs zonation; for example, mice with deletions of key Wnts such as Wnt2 and Wnt9b, or Wls, a gene encoding a chaperone required for Wnt ligand secretion, exhibit profound disturbances in hepatocyte zonation (85, 86). Similarly, mice with hepatocyte-specific deletion of β-catenin lose zonation and display widespread metabolic abnormalities (87–91). Clarifying the roles of specific Wnt ligands, modulators, receptors, and downstream targets in MASLD pathogenesis remains a key research priority.

Hepatocyte zonation. Pioneering studies in the latter half of the 20th century, using in situ hybridization and immunohistochemistry, revealed that hepatocyte gene expression is not uniform. These early investigations proposed a model in which opposing metabolic processes are segregated by hepatic zones (92). For example, glucose production via gluconeogenesis occurs predominantly in zone 1, while glucose consumption through glycolysis is concentrated in zone 3. Similarly, glutamine is catabolized in zone 1 but synthesized in zone 3, and cholesterol synthesis is localized to zone 1, whereas bile acid production occurs primarily in zone 3.

Advances in molecular techniques greatly expanded the number of identified zonated genes. In 2006, Brauening et al. used bulk RNA sequencing of pericentral and periportal hepatocytes to identify approximately 200 differentially expressed genes (93). More recently, single-cell and single-nucleus profiling have revolutionized our understanding, demonstrating that 40%–50% of hepatocyte transcripts exhibit zonation (94). Thus, zone 1 and zone 3 have distinct transcriptional profiles, highlighting their specialized and divergent metabolic functions.

Hepatocyte organelles also exhibit zonal variation, with mitochondria being the most extensively studied. Building on earlier electron microscopy observations, recent work by Kang and colleagues demonstrated that mitochondria in zone 1 hepatocytes have greater mass and are morphologically distinct from their counterparts in zone 1 (95). In vitro studies using fluorescence-activated cell sorting further revealed that zone 1 mitochondria exhibit higher oxygen consumption rates and transmembrane potential. Additionally, zone 1 hepatocytes showed elevated ATP levels and increased sensitivity to etomoxir, a mitochondrial fatty acid oxidation inhibitor. These findings suggest that zone 1 mitochondria are specifically adapted for fatty acid oxidation and glucose production, key metabolic functions of this region.

Hepatocyte signaling also varies substantially between zones. Kubota et al. demonstrated that IRS1 and IRS2 — key components of the insulin signaling pathway, though not the insulin receptor itself — are differentially distributed, with IRS1 enriched in zone 3 and IRS2 predominating in zone 1, suggesting zonal differences in insulin responsiveness (96). Similarly, Cangelosi et al. found that zone 1 hepatocytes have a greater capacity to sense and respond to the amino acid leucine compared with those in zone 3 (97). Additionally, unbiased phosphoproteomic analysis revealed distinct phosphorylation patterns between zone 1 and zone 3 hepatocytes, indicating differences in kinase and phosphatase activity (95). Collectively, these findings demonstrate that hepatocytes are not only metabolically distinct across zones but also exhibit compartmentalized signaling responses, allowing each zone to be finely tuned to specific physiological or environmental stimuli.

Nonparenchymal cells. Emerging evidence suggests that transcriptional profiles and the composition of nonparenchymal cells vary substantially across liver zones. Immunohistochemical studies from the 1990s first reported an increased presence of immune cells in the periportal region. More recently, spatial proteogenomics has revealed higher numbers of Kupffer cells in zone 1 (98). One emerging theme is the role of gut microbes in shaping the immune microenvironment of zone 1. Gola and colleagues demonstrated that Kupffer cell predominance in zone 1 was diminished in germ-free mice and in those with disrupted inflammatory signaling in LSECs, suggesting that gut microbiota signal through LSECs to establish chemokine gradients that recruit or retain immune cells in LSECs (99). Similarly, Miyamoto and colleagues identified a distinct population of tolerogenic macrophages enriched in zone 1, characterized by high expression of MARCO1, a scavenger receptor for proinflammatory pathogen-associated molecular patterns and damage-associated molecular patterns (100). This macrophage population relied on signals from commensal gut microbes, particularly Odoribacteraceae, via the microbial metabolite isoallolithocholic acid (100).

The transcriptional profiles of other nonparenchymal cells, including LSECs (101) and HSCs (102), also vary by zone. Notably, zone 3 HSCs play a predominant role in collagen production following chronic carbon tetrachloride injury, suggesting functional distinctions between stellate cells in zones 1 and 3 (102). These findings highlight the influence of zonal microenvironments in shaping nonparenchymal cell behavior, with important implications for liver injury and repair.

Functional implications. Understanding hepatic zonation not only reveals mechanistic underpinnings of MASLD but also highlights its functional implications, including how zonal differences influence lipid metabolism, immune responses, and disease progression. Zone 1 and zone 3 of the liver are defined by distinct microenvironments, cellular compositions, and functional states. Among hepatocytes, differences have been documented in epigenetics (103), signaling (95), transcriptomic profiles (94), and metabolite profiles (104). These insights offer a novel framework for understanding the pathophysiological differences between pediatric and adult MASLD.

Hepatic triglyceride accumulation in MASLD is partly driven by excessive de novo lipogenesis, a process dependent upon insulin signaling (105, 106). However, the greater susceptibility of zone 3 hepatocytes to lipid accumulation and injury in adult MASLD remains unclear. One hypothesis suggests that insulin preferentially activates lipogenic pathways in zone 3, as IRS1, which is more closely linked to lipogenesis, is more highly expressed in this zone (96). Alternatively, zone 1 hepatocytes, exposed to higher concentrations of free fatty acids, may accumulate more ceramides, reducing insulin signaling and lipogenesis compared with zone 3 hepatocytes (107).

The prominence of zone 1 involvement in pediatric MASLD suggests additional mechanisms driving lipid accumulation in this population. Elevated β-oxidation activity in zone 1 indicates that these hepatocytes may rely more heavily on this pathway to regulate triglyceride levels. Supporting this, mice with impaired β-oxidation exhibit increased periportal steatosis (108). Thus, early life insults that compromise β-oxidation, such as mitochondrial dysfunction, could be more important drivers of pediatric MASLD. Alternatively, microbial insults that disrupt the immune compartment in zone 1 could be key contributors.

Deciphering these mechanisms requires detailed analysis of pediatric liver tissue, as much of what is known about zonation comes from mouse and adult human studies. Fortunately, advancements in single-cell profiling of epigenetics, gene expression, protein expression, and metabolites are rapidly improving both the quantity and quality of data from limited samples (109). Given the limited availability of biopsy specimens from pediatric patients, fostering collaboration and promoting resource sharing within the research community will be essential to leveraging these technologies and accelerating progress in understanding pediatric MASLD.

In summary, pediatric MASLD is a distinct clinical and pathological entity driven by a complex interplay of genetic, metabolic, perinatal, and environmental factors. This Review has highlighted the multifactorial nature of the disease, emphasizing how its earlier onset compared with adult MASLD reflects unique developmental vulnerabilities and mechanistic pathways. Affecting approximately 1 in 10 children, pediatric MASLD is both common and severe, with a substantial proportion of cases progressing to advanced disease, posing long-term liver health risks and a significant public health burden. Epidemiological disparities — including variations in prevalence across age, sex, and racial or ethnic groups — highlight the critical need for tailored prevention and intervention strategies to address these challenges effectively.

Perinatal factors, including maternal health, gestational diabetes, and early-life nutritional exposures, play a crucial role in shaping disease risk, with epigenetic modifications driving metabolic programming. Genetic predispositions, such as variants in PNPLA3 and TM6SF2, further compound this risk, particularly when interacting with early-life stressors. Additionally, the predominance of zone 1 inflammation and fibrosis in pediatric MASLD provides critical insights into the spatial and functional heterogeneity underlying disease progression.

As detailed in Table 1, advancing the field will require a multifaceted approach integrating research, clinical innovation, and public health initiatives. Key priorities include developing pediatric-specific diagnostic tools, identifying mechanisms of disease progression, and translating these insights into targeted therapies (110). Equally important is addressing broader social and environmental determinants, such as maternal health and early-life nutrition, which shape MASLD risk from infancy. By prioritizing these efforts, the field can move toward actionable strategies to reduce disease burden, improve patient outcomes, and ultimately mitigate the public health impact of pediatric MASLD.

Table 1

Research priorities in pediatric MASLD

The authors gratefully acknowledge grant support from the NIH, including R01DK135951, R01DK133198, and U01DK61734 (to JBS); R01DK125898 and R01DK134647 (to SBB); and R01DK122948 and P30DK084567 (to SHI). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Address correspondence to: Jeffrey B. Schwimmer, Department of Pediatrics, UCSD and Rady Children’s Hospital San Diego, 3020 Children’s Way, MC 5030, San Diego, California, 92123, USA. Phone: 858.966.8905; Email: jschwimmer@health.ucsd.edu.

Conflict of interest: JBS reports grant support to the University of California, San Diego, from Seraphina Therapeutics and Thiogenesis Therapeutics.

Copyright: © 2025, Freiwald et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Reference information: J Clin Invest. 2025;135(13):e186422. https://doi.org/10.1172/JCI186422.

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