Search Results (4,593)

Background/Objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD), previously known as non-alcoholic fatty liver disease (NAFLD), is the most prevalent chronic liver disease worldwide, affecting approximately 25% of the global population. MAFLD represents a broad disease spectrum ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The availability of experimental models that faithfully reproduce human metabolic and hepatic pathology is essential for elucidating disease mechanisms and advancing therapeutic development. This review aims to critically evaluate commonly used rodent models of MAFLD and provide guidance for model selection based on specific research objectives. Methods: A narrative, semi-systematic literature search was performed using PubMed Central, Ovid MEDLINE, and Google Scholar. Rodent models were classified according to their mode of disease induction, including diet-induced, genetically engineered, chemically or pharmacologically induced, and combination models. Models were assessed based on frequency of use, relevance to different stages of MAFLD progression, metabolic fidelity, and suitability for mechanistic studies and preclinical therapeutic evaluation. Results: Diet-induced models incorporating high fat, fructose, and cholesterol most closely recapitulate human metabolic dysfunction and are highly relevant for translational research and drug screening. Nutrient-deficient diets induce rapid steatohepatitis and fibrosis but lack key features of metabolic syndrome. Genetic models enable the targeted interrogation of specific metabolic and inflammatory pathways, whereas chemical and combination models accelerate fibrosis and HCC development. No single rodent model fully reproduces the entire spectrum of human MAFLD. Conclusions: Rodent models remain indispensable tools for MAFLD research; however, their applicability depends on alignment with the defined experimental goals. Careful selection of models based on disease stage, dominant pathogenic mechanisms, and translational intent is essential for improving reproducibility and clinical relevance. This review provides a practical framework to guide investigators in choosing appropriate preclinical models for mechanistic studies and therapeutic development in MAFLD. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of global chronic liver disease, with a prevalence of approximately 30%. This review outlines the diagnostic transition from the exclusionary non-alcoholic fatty liver disease (NAFLD) framework to the affirmative MASLD nomenclature, which mandates the presence of at least one of five specific cardiometabolic risk factors (CMRFs) to prioritize active pathophysiology. Beyond hepatic complications, MASLD drives systemic metabolic failure, significantly elevating risks for type 2 diabetes, hepatocellular carcinoma, and cardiovascular disease, the primary cause of mortality in this cohort. Clinical management relies on a standardized, two-tier risk-stratification pathway for advanced fibrosis. Primary care triage utilizes the Fibrosis–4 (FIB–4) index; a score < 1.3 excludes advanced disease via a high negative predictive value, whereas indeterminate or high scores require secondary validation via vibration-controlled transient elastography (VCTE) or the enhanced liver fibrosis (ELF) test to guide specialist referral. Although lifestyle modifications, principally a 7–10% weight reduction and Mediterranean diet adherence, remain foundational, management has transitioned toward disease-modifying pharmacotherapies. A pivotal breakthrough occurred with the 2024 FDA approval of resmetirom, a selective thyroid hormone receptor-beta (THR-β) agonist, for non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate-to-advanced fibrosis. Concurrently, the emergence of GLP-1 receptor agonists and multi-incretin mimetics offers a personalized, multi-target approach simultaneously addressing hepatic inflammation, glycemic control, and adiposity. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent in patients with type 2 diabetes (T2D) and is associated with increased cardiovascular risk. However, the relative contribution of traditional cardiometabolic risk factors (CMRFs), hepatic fibrosis markers, and antidiabetic therapies to atherosclerosis remains unclear. Methods: We conducted a cross-sectional study including 46 patients with T2D and MASLD. Atherosclerotic cardiovascular disease (ASCVD) was defined as the presence of carotid atheromatosis, stroke, peripheral arterial disease, or ischemic heart disease, as assessed by imaging-based parameters. Clinical, metabolic, and treatment-related variables were analyzed, including age, Hemoglobin A1c (HbA1c), lipid profile, hepatic fibrosis indices such as Fibrosis-4 index (FIB-4), and antidiabetic therapies (sodium–glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and insulin). Multivariable regression models and receiver operating characteristic (ROC) curve analyses were used to evaluate associations and discriminative performance. Results: Traditional CMRFs were more strongly associated with ASCVD than hepatic fibrosis markers or antidiabetic therapies. Age was associated with ASCVD in several exploratory models, although this association was attenuated in the fully adjusted model. HbA1c showed the highest discriminative performance (AUC 0.77), indicating that chronic glycemic exposure is a major determinant of vascular disease in this cohort. In contrast, FIB-4 was not associated with ASCVD and did not improve model performance. Antidiabetic therapies, including SGLT2i and GLP-1 RAs, were not independently associated with ASCVD. Insulin therapy was more frequent among patients with ASCVD, but was not independently associated after adjustment. Conclusions: In patients with T2D and MASLD, ASCVD appears to be associated with traditional CMRFs, particularly chronic glycemic exposure, rather than hepatic fibrosis markers or treatment status. These findings highlight the central role of metabolic control in cardiovascular risk and suggest that the contribution of liver-related markers and therapeutic interventions may be more relevant in longitudinal settings. Full article

Cyanidin-3-O-Glucoside (C3G) is the primary anthocyanin-active component in bilberry, exhibiting various pharmacological activities such as antioxidant, anti-inflammatory, and lipid metabolism-regulating effects. To address the clinical need for non-alcoholic fatty liver disease (NAFLD) prevention and treatment, this study aimed to investigate the ameliorative effects of C3G on NAFLD pathology and elucidate its molecular mechanisms of protection via the AMPK pathway. After a one-week acclimatization period, 20 six-week-old SPF mice were randomly divided into four groups: normal diet control (NCD), high-fat diet model (HFD), HFD + L-C3G (100 mg/kg/day), and HFD + H-C3G (200 mg/kg/day). Except for the NCD group, the remaining groups were fed a 60% high-fat diet for four weeks to establish an early-stage NAFLD model, with successful model construction verified by weight and liver weight gain. From the fifth week onward, C3G groups received daily administration for four consecutive weeks, while control groups were given an equal volume of distilled water. Liver function, lipid metabolism, oxidative stress, and inflammatory levels were assessed using ELISA, H&E staining, and other methods. The results showed that C3G restored liver function in NAFLD mice, improved lipid metabolism disorders, reduced oxidative stress and inflammatory responses, and alleviated liver pathological damage. Mechanistic studies revealed that C3G regulated the expression of mRNA and proteins related to the AMPK/SIRT1/NF-κB signaling pathway, activating the pathway by upregulating AMPK and its upstream regulators while inhibiting NF-κB-mediated inflammatory responses. This study confirmed that C3G can ameliorate high-fat diet-induced NAFLD lesions by activating the AMPK/SIRT1/NF-κB pathway, providing a potential intervention strategy for NAFLD prevention and treatment. Full article

This translational synthesis highlights the potential role of obesity-induced low-grade chronic inflammation in modulating clinical outcomes among patients with spondyloarthritis (SpA). Obesity transforms adipose tissue into a pro-inflammatory endocrine organ, where hypertrophic adipocytes release adipokines such as leptin alongside cytokines including TNF-α and IL-6, potentially contributing to macrophage polarization toward an M1 phenotype and activating NF-κB signaling pathways. This systemic immunometabolic priming may lower activation thresholds at the enthesis—the primary pathological site in SpA—potentially amplifying IL-23/IL-17 axis activity via Th17 bias, innate-like lymphocyte responses, and stromal–immune crosstalk under mechanical stress. Clinically, patients with SpA and obesity have been reported to demonstrate heightened disease activity (BASDAI, ASDAS), impaired function (BASFI), accelerated radiographic progression (syndesmophytes, enthesophytes), and diminished biologic response rates, potentially attributable to pharmacokinetic alterations (e.g., subtherapeutic TNF inhibitor levels) and pharmacodynamic resistance. Multisystem comorbidities, including non-alcoholic fatty liver disease, cardiovascular events, metabolic syndrome, sleep disturbances, and depression, further exacerbate morbidity and diminish quality of life. Therapeutic implications emphasize obesity as a modifiable disease modifier. Weight loss interventions, including hypocaloric diets, anti-inflammatory regimens (e.g., Mediterranean diet), multicomponent exercise, GLP-1 receptor agonists, and bariatric surgery, have been associated with reductions in inflammatory biomarkers, improved remission rates (MDA, DAPSA), and prolonged drug survival by restoring adipokine balance and disrupting mechano-inflammatory loops. Future randomized controlled trials should prioritize long-term evaluations of integrated multidisciplinary strategies that combine metabolic optimization with immunomodulatory therapies, addressing adherence challenges through psychological support and patient-tailored protocols, while elucidating dose–response relationships for GLP-1RAs and exercise in diverse SpA subtypes to establish precision management paradigms that mitigate cardiometabolic burden and improve holistic outcomes. Full article

Dysfunction-associated steatotic liver disease (MASLD) is a newly introduced term for the condition previously known as nonalcoholic fatty liver disease (NAFLD). MASLD affects 38% of the global population and is now diagnosed based on the presence of steatosis but also with cardiometabolic risk factors indicating metabolic dysfunction. Chronic hepatitis B (CHB), another significant public health issue, impacts over 296 million people worldwide, or approximately 3.2% of the global population. Studies have consistently reported a complex relationship between MASLD and CHB. Previous studies indicate that MASLD may protect against high viral loads, while other studies indicate that coexisting MASLD and CHB may lead to more advanced fibrosis and an elevated risk of HCC. Additionally, numerous studies highlight a strong association between CHB and metabolic syndrome components. This review article examines the relationship between CHB and MASLD, considering what has been previously published. Full article

Chronic intermittent hypoxia (CIH), the cardinal pathophysiological feature of obstructive sleep apnea, is increasingly recognized as an important modifier of metabolic dysfunction-associated steatotic liver disease (MASLD), but the underlying mechanisms remain incompletely understood. In this study, male C57BL/6 mice were fed a standard diet or a high-fat diet (HFD) and exposed to normoxia or CIH for 8 weeks. Histological, ultrastructural, biochemical, transcriptomic, proteomic, and metabolomic analyses were integrated to characterize hepatic alterations induced by CIH under metabolic stress. CIH markedly aggravated HFD-induced liver injury, as evidenced by increased body fat, hepatomegaly, serum transaminases, steatosis, mitochondrial ultrastructural alterations, and inflammatory infiltration. Mechanistically, CIH promoted hepatic lipid metabolic reprogramming by suppressing the PPARα/CPT1A fatty acid β-oxidation axis while enhancing the SREBP-1c/FASN/PLIN2 lipogenic pathway, impaired the Nrf2/HO-1/SLC7A11/GPX4 antioxidant defense system, increased lipid peroxidation and iron accumulation, and activated NF-κB/NLRP3 signaling. These findings support a multifactorial model in which CIH functions as an additional hypoxic stressor that exacerbates HFD-induced MASLD-like liver injury through coordinated metabolic, oxidative, and inflammatory dysregulation. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the leading cause of chronic liver disease globally, mirroring the increasing prevalence of obesity, insulin resistance, and type 2 diabetes. Early detection of hepatic steatosis is vital for cardiometabolic risk assessment; however, conventional imaging is costly and impractical for population screening. This study aimed to develop interpretable machine-learning models to predict ultrasound-detected hepatic steatosis within the MASLD spectrum using routinely available clinical and biochemical data. Methods: We analyzed data from 644 adults, 50% of whom had ultrasound-detected hepatic steatosis. Preprocessing, imputation, and feature selection were implemented within a single scikit-learn pipeline to avoid information leakage. An Elastic Net-regularized logistic regression identified the top 20 predictors, which were subsequently used across nine supervised machine learning (ML) classifiers. Model performance was evaluated via repeated stratified 5-fold cross-validation (25 resamples) using accuracy, F1 score, sensitivity, specificity, Youden’s J, balanced accuracy, and Area Under the Receiver Operating Characteristic Curve (AUROC). Interpretability was assessed using SHapley Additive exPlanations (SHAP). Results: Participants with ultrasound-detected hepatic steatosis exhibited greater adiposity, insulin resistance, and dyslipidemia compared with controls [p < 0.05 for body mass index (BMI), waist circumference, glucose, glycated hemoglobin (HbA1c), triglycerides]. Elastic Net selection highlighted Weight, Ponderal Index, Fibrosis-4 Index (FIB-4), blood urea nitrogen (BUN)/Creatinine ratio, Aspartate Aminotransferase to Platelet Ratio Index (APRI), and Visceral Adiposity Index as the strongest predictors. Logistic Regression and Gradient Boosting achieved the best performance (accuracy = 0.65 ± 0.03; AUROC = 0.71 ± 0.04; balanced accuracy = 0.66 ± 0.06), outperforming rule-based indices such as Fatty Liver Index (FLI) and Hepatic Steatosis Index (HSI) reported in the literature. SHAP analysis confirmed clinically coherent feature effects, with higher anthropometric and hepatic injury indices increasing the predicted probability of ultrasound-detected hepatic steatosis. Conclusions: Routinely available clinical and biochemical parameters can predict hepatic steatosis with moderate accuracy using transparent, interpretable ML models. Logistic Regression and Gradient Boosting provided best discrimination and robust internal performance, offering a pragmatic, low-cost approach for early identification of ultrasound-detected hepatic steatosis within the MASLD spectrum in primary and metabolic care settings. Full article

The liver circadian clock coordinates hepatic lipid metabolism, bile acid synthesis, and glucose homeostasis through interlocking transcription–translation feedback loops. Disruption of this temporal organization is increasingly recognized as a shared pathological feature across the chronic liver disease spectrum. Transcriptomic profiling alone cannot capture the full scope of circadian dysregulation. Approximately half of rhythmically abundant hepatic proteins lack correspondingly rhythmic mRNAs. Roughly 25% of hepatic phosphosites oscillate with a 24-h period. Integrating transcriptomics, proteomics, post-translational modification profiling, metabolomics, and emerging single-cell and spatial approaches is therefore necessary for an accurate account of how circadian programs are remodeled in disease. This narrative review delineates the multi-omics landscape of circadian clock dysregulation across six chronic liver disease categories. These encompass metabolic dysfunction-associated fatty liver disease (MAFLD), alcoholic liver disease (ALD), viral hepatitis, hepatocellular carcinoma (HCC), liver fibrosis, and cholestatic disease. Four molecular features recur across these contexts. BMAL1 functional downregulation, REV-ERBα oscillatory output attenuation, NAD⁺ oscillatory amplitude reduction, and gut–liver axis circadian desynchronization together constitute an inferential framework for hepatic circadian failure. These features represent recurring disease-associated motifs rather than an established pan-disease mechanism. The upstream mechanisms and evidence depth differ substantially by disease category. Oncogenic kinase-driven CLOCK post-translational modifications in HCC, phosphoproteomic remodeling in MAFLD, and epigenomic clock disruption persisting after HCV clearance represent findings that transcriptomics alone would not resolve. The near-complete absence of temporally resolved human tissue data remains the principal barrier to translational progress. This evidence gap limits the clinical actionability of current mechanistic findings across all disease categories. Circadian phase inference algorithms and prospective temporally designed cohort studies offer a methodologically grounded path toward clinically actionable circadian hepatology. Full article

The occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD) are closely related to intestinal flora imbalance, intestinal barrier damage, and gut-liver axis dysfunction. Due to their multi-target regulatory effects and advantages in intestinal microecological intervention, Chinese herbal monomers have shown promising application prospects in the prevention and treatment of MASLD. However, basic research on their toxicity still lags behind, and issues related to safety and clinical translation urgently need attention. This article systematically reviews the research progress on how flavonoids, triterpenoids, alkaloids, and polysaccharides improve hepatic steatosis, inflammatory responses, and metabolic disorders from a toxicological perspective by reshaping the intestinal microbiota, repairing the intestinal mucosal barrier, regulating short-chain fatty acid and bile acid metabolism, and synergistically acting on signaling pathways such as TLR4/NF-kB, FXR, TGR5, SIRT1, and the NLRP3 inflammasome. Furthermore, by combining methods such as 16S rRNA sequencing, metagenomics, metabolomics, and multi-omics integration, the article analyzes their application value and limitations in toxicological mechanism research, and discusses the translational bottlenecks faced by Chinese herbal monomers in pharmacokinetics, bioavailability, quality standardization, targeted delivery, and toxicological safety. Existing evidence indicates that Chinese herbal monomers have a three-in-one intervention advantage of microecological remodeling-metabolic regulation-inflammation inhibition, but their long-term medication safety, toxic target organs, dose-effect/toxicity relationships, and potential drug interactions still need further clarification. This article aims to provide a systematic reference for the safety evaluation and clinical translational research of Chinese herbal monomers in the prevention and treatment of MASLD. Full article

Background/Objectives: Visit-to-visit glycated hemoglobin A1c (HbA1c) variability is associated with cardiovascular diseases (CVDs) and all-cause mortality, independent of mean HbA1c levels. Metabolic dysfunction–associated steatotic liver disease (MASLD) is associated with CVDs and mortality. We aimed to clarify the association between annual HbA1c variability and MASLD development in individuals with type 2 diabetes (T2D). Methods: A retrospective cohort study was conducted in 402 Japanese patients (219 men, 183 women) with T2D. The participants’ HbA1c levels were measured every 2 months, and their HbA1c coefficient of variation (HbA1c-CV) was calculated from the HbA1c in the past year. We statistically evaluated the association between HbA1c-CV and noninvasive clinical indices of MASLD, including the hepatic steatosis index (HSI), fibrosis-4 (FIB-4) index, aspartate aminotransferase-to-platelet ratio index (APRI), and non-alcoholic fatty liver disease fibrosis score (NFS). Results: Multiple regression analysis of clinical variables and each MASLD index showed that all liver fibrosis indices, including the FIB-4 index (p < 0.001), APRI (p = 0.005), and NFS (p < 0.001), were positively correlated with HbA1c-CV, whereas the HSI was not (p = 0.148). These associations remained even after adjusting for the medications used in the participants. Conclusions: The development of liver fibrosis, estimated using noninvasive blood biochemical indices, is independently and positively associated with annual HbA1c-CV in individuals with T2D. This result suggests that a comprehensive approach, including early MASLD risk stratification, may be beneficial for optimal diabetes management. Full article

Background/Aim: Routine ultrasonography now detects gallbladder polyps (GBPs) more often, but reported prevalence varies across populations. Jeju Island has South Korea’s highest obesity prevalence and red meat consumption, suggesting a rapid nutritional transition similar to that reported in Native Hawaiians. This study aimed to first analyze risk factors influencing GBP prevalence, including birthplace, and second compare clinical variables between JNs and JMs. Methods: Between May 2018 and October 2023, 28,751 individuals underwent medical checkups at Jeju National University Hospital. GBPs were diagnosed via ultrasonography, and risk factors including age, sex, birthplace, metabolic syndrome, hepatitis B virus antigen (HBsAg) positivity, lipid profiles, and alcohol consumption were assessed using univariate and multivariate logistic regression. Results: After exclusions, 15,219 participants were analyzed. The overall prevalence of GBPs was 10.3%. Male participants had a higher prevalence than females (11.4% vs. 9.1%, p < 0.001). The younger age group (20–49 years) showed the highest prevalence, while those aged ≥70 years had the lowest (11.6% vs. 8.6%, p = 0.001). Jeju Natives (JNs) exhibited a significantly higher prevalence than Jeju migrants (JMs) (10.6% vs. 9.0%, p = 0.004). Multivariate analysis identified female sex [odds ratio (OR) = 0.644, p < 0.001], age ≥ 70 years (OR = 0.601, p < 0.001), JN birthplace (OR = 1.260, p = 0.015), HBsAg positivity (OR = 1.347, p = 0.040), and high-risk alcohol drinking (OR = 0.758, p = 0.001) as independent predictors. Notably, the 60–69 age group did not reach statistical significance in the optimized model (p = 0.158). Compared to JMs, JNs were older and had a higher prevalence of fatty liver disease, a higher BMI, and higher levels of AST and GGT, but lower levels of HDL-cholesterol and triglycerides. Conclusions: GBPs are more prevalent among JNs compared to JMs, with birthplace emerging as a novel independent risk factor. Fatty liver disease, BMI, and reduced HDL-cholesterol were associated with GBP risk. These findings hypothesize that dietary and metabolic health factors may be potential pathways for the higher GBP prevalence among JNs, though direct dietary assessment is required for confirmation. Full article

Obesity contributes to an increase in the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and is diagnosed when hepatic steatosis is accompanied by at least one of the following factors: obesity or overweight, diabetes mellitus, or signs of metabolic abnormalities. MAFLD is a term that encompasses a wide range of liver disorders, ranging from simple steatosis to metabolic steatohepatitis, which can progress to cirrhosis and eventually, hepatocellular carcinoma (HCC). Lipotoxicity generated by a high-fat diet causes liver inflammation, therefore, blocking inflammatory pathways is considered a promising strategy to prevent MAFLD progression. Inflammatory responses and oxidative stress are linked to endoplasmic reticulum stress, thereby activating the unfolded protein response (UPR) pathway. Although drugs such as resmetirom and semaglutide have recently been approved for the treatment of MAFLD, there is still a need to identify complementary therapies with different mechanisms of action. In this context, the present study evaluated the hepatoprotective effect of ellagic acid through the modulation of mRNAs of proteins in the UPR-Perk pathway in a murine model fed a high-calorie diet. This study revealed that the high-calorie diet activated the UPR pathway in response to stress, increasing the expression of the Grp78, Eif2ak3, Eif2α, Ddit3, Atf4, and Nfe2l2 genes in the liver and epididymal adipose tissue. Ellagic acid modulated the pathway genes and reduced levels of glucose, total cholesterol, HDL and VLDL, triglycerides, insulin, and glycated hemoglobin, and could therefore be considered a hepatoprotective agent. Full article

Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by abnormal hepatic lipid accumulation and is frequently driven by factors such as a high-fat diet (HFD). Total flavonoids of Apocynum venetum (TFAV), the bioactive constituents of a traditional medicinal plant, have demonstrated antioxidant and lipid-modulating properties. However, their therapeutic potential against MASLD and the underlying mechanisms are not explored. This study aims to evaluate the ameliorative effects of TFAV on HFD-induced MASLD utilizing both in vivo animal and in vitro cellular models. Methods: C57BL/6J were allocated to control, high-fat diet (HFD), TFAV (100 mg/kg/day), and TFAV intervention groups (25, 50, and 100 mg/kg/day). In vitro, WRL68 hepatocytes were stimulated with free fatty acids (FFAs) to establish a cellular model of steatosis. Liver function, serum lipid profiles, hepatic histopathology, and the AMPK signaling pathway were assessed. Results: TFAV intervention significantly improved serum biochemical profiles in the animal models; for instance, co-treatment with 100 mg/kg/day TFAV and HFD reduced TC, TG, and LDL-C levels by 20.59%, 45.26%, and 38.24% respectively (p < 0.05), and effectively alleviated hepatic steatosis and hepatocyte ballooning. Furthermore, TFAV markedly inhibited intracellular reactive oxygen species (ROS) levels and activated the AMPK signaling pathway (p < 0.05). This was accompanied by the downregulation of SREBP-1c and ACC expression (p < 0.05), as well as the upregulation of ATGL and CPT1α expression (p < 0.05). Conclusions: These results demonstrates that TFAV remodel hepatic lipid homeostasis by activating the AMPK signaling pathway, and exerting significant preventive and protective effects against the progression of HFD-induced MASLD in vivo. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread condition with a complex pathogenesis. Cell-based models are important tools for studying the mechanisms underlying its development and progression. The aim of this review is to analyze the HepaRG, Huh-7, immortalized human hepatocyte (IHH), and primary human hepatocyte (PHH) cell lines for modeling and studying MASLD. HepaRG represents the most metabolically competent immortalized hepatocyte model with preserved biotransformation activity and a physiological bioenergetic response to lipid loading, making it valuable for pharmacological and toxicological studies. Huh-7 is distinguished by its accessibility and suitability for studying steatosis, lipotoxicity, insulin resistance, and paracrine mechanisms of fibrogenesis; however, its use is limited by its tumor origin, impaired carbohydrate metabolism, and low activity of xenobiotic-metabolizing enzymes. The IHH model occupies an intermediate position because of its non-tumor origin and is of interest for studies of senescence, epigenetic regulation, and signaling pathways involved in steatosis, although interpretation of results requires consideration of immortalization-related effects and specific metabolic limitations. PHH remains the most physiologically relevant platform for MASLD modeling, particularly in three-dimensional (3D) and microphysiological formats; however, its use is limited by high cost, interindividual variability, and the limited duration of the differentiated phenotype. Increasing model complexity—from two-dimensional (2D) monocultures to co-cultures, spheroids, and organ-on-chip systems—enhances physiological relevance and enables reproduction not only of steatosis but also of the inflammatory and fibrogenic components of MASLD progression, yet it reduces reproducibility and complicates standardization. Overall, none of the existing models is universal, and the optimal strategy is to select models according to the specific research question. A key direction for future research is the standardization of steatosis induction protocols and the unification of criteria for evaluating results. Full article