From Pathophysiological Consensus to Integrative Potential: A Comprehensive Narrative Review of Traditional Chinese Medicine Interventions for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Future Directions

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, is the most prevalent chronic liver disease globally, with a worldwide prevalence over 30%. Its complex pathogenesis involves insulin resistance, lipid metabolism disorders, mitochondrial dysfunction, gut-liver axis imbalance, chronic inflammation and genetic susceptibility. Currently, no radical pharmacological treatment is clinically approved for MASLD, resulting in a huge unmet clinical demand. Traditional Chinese Medicine (TCM) presents unique strengths in multi-target regulation and long-term prognosis improvement for MASLD, yet fragmented mechanistic evidence and inconsistent syndrome differentiation criteria limit its international application. This narrative review systematically summarizes the latest epidemiological, pathophysiological and diagnostic progress of MASLD, and clarifies the internal correlation between TCM theories and modern pathological mechanisms. Relevant domestic and foreign literature published from 2015 to 2025 was retrieved and analyzed to compare the advantages and limitations of Western medicine and TCM interventions. Western medicine mainly adopts lifestyle intervention, targeted drugs and bariatric surgery, while TCM therapies including herbal formulas, active ingredients, acupuncture and moxibustion improve MASLD through regulating lipid metabolism, stabilizing intestinal microecology, inhibiting inflammation and modulating hepatocyte autophagy, with reliable clinical efficacy. Nevertheless, non-uniform quality standards and insufficient high-level clinical trials restrict the standardized development of TCM. In conclusion, TCM’s holistic and multi-target characteristics perfectly adapt to the multifactorial pathogenesis of MASLD. Future studies should combine multi-omics and precision medicine to unify TCM diagnostic and pharmaceutical standards and conduct high-quality multicenter trials, promoting the standardization and international popularization of TCM in MASLD management.

Introduction

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a hepatic disorder closely linked to systemic metabolic disorders. It has reached pandemic proportions across the globe, with an estimated global prevalence exceeding 30%,¹ affecting people of all age groups and various special populations and imposing substantial socioeconomic and public-health burdens worldwide. Frequently accompanied by multisystem complications including type 2 diabetes, dyslipidaemia and cardiovascular diseases, MASLD poses a severe threat to public health.¹ Although promising therapeutic candidates such as resmetirom have demonstrated efficacy in Phase III clinical trials, practical limitations remain: restricted real-world accessibility together with treatment-related adverse events including diarrhoea and nausea hinder broad clinical application, and no pharmacotherapy has gained universal clinical approval for general MASLD populations, resulting in prominent unmet clinical needs.

In 2023, an international consensus issued by hepatology professionals officially renamed the traditional Non-Alcoholic Fatty Liver Disease (NAFLD) to Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).¹ The removal of the “non-alcoholic” definition highlights metabolic dysfunction as the core driving factor of the disease. This nomenclature revision is not merely a standardization of medical terms; it also exerts a profound impact on syndrome differentiation, pathogenesis interpretation and clinical research design in traditional Chinese medicine (TCM).² Traditional studies on MASLD mainly focused on the pathogenesis of phlegm-dampness, liver depression and spleen deficiency.² In contrast, MASLD emphasizes the central role of systemic metabolic imbalance and gut-liver axis dysfunction, which is highly consistent with the TCM theories that the spleen governs transportation and transformation, the liver governs qi movement, and phlegm, dampness and blood stasis intermingle.² This shift helps refine the TCM syndrome differentiation criteria for MASLD and promotes the integration of pathogenesis theories between Chinese and Western medicine.

This article systematically reviews the epidemiological characteristics and risk factors of MASLD, and elaborates on its molecular mechanisms and genetic background underlying disease onset and progression. It also presents the current application of non-invasive diagnostic approaches including imaging techniques and biomarkers. Meanwhile, Western medical interventions such as pharmacotherapy, lifestyle modification and bariatric surgery are comparatively discussed, with special attention paid to the gaps in available pharmaceutical options. Focusing on the theoretical basis and clinical practice of TCM, this paper summarizes the unique strengths of TCM in regulating lipid metabolism, intestinal flora and inflammatory responses, further justifying the clinical value of integrative TCM strategies for MASLD. Finally, the existing controversies regarding TCM treatment are pointed out, and future development directions integrating precision medicine, multi-omics technologies and internationalization are prospected. This review provides a comprehensive reference for the full understanding and combined management of MASLD.

Epidemiology

The global prevalence of MASLD has emerged as a significant public health concern, and its incidence is closely linked to economic development and lifestyle modifications. A meta-analysis encompassing 21 population-based studies reported an overall global MASLD prevalence of 24.24%, demonstrating a significant positive correlation with gross national income (GNI).¹ Regional disparities are notable, with Europe exhibiting the highest prevalence rate at 28.04%, significantly exceeding rates observed in the Middle East and East Asia.¹ Sex differences were also pronounced, as males exhibited higher prevalence rates than females, particularly within European and Caucasian cohorts.¹ Notably, the association between MASLD prevalence and economic status is more pronounced in rural areas than in urban settings, implying that lifestyle changes accompanying urbanization may not be the sole contributing factor.¹

The burden of MASLD among the pediatric and adolescent populations is comparably severe. Research indicates that childhood obesity is a critical risk factor for MASLD, with overweight or obese children displaying markedly increased incidence rates, often accompanied by metabolic disturbances, such as dyslipidemia, hypertension, and insulin resistance.² In particular, the Asia-Pacific region has witnessed a pronounced increase in obesity prevalence, paralleling an increase in MASLD and related metabolic disorders, including diabetes.³ Furthermore, the global prevalence of metabolic syndrome among patients reaches 42.54%, with obesity (51.34%), type 2 diabetes (22.51%), hyperlipidemia (69.16%), and hypertension (39.34%) representing the most common comorbidities.⁴ These findings underscore that MASLD should no longer be regarded solely as a hepatic condition, but rather as a hepatic manifestation of systemic metabolic dysfunction, necessitating its integration into comprehensive metabolic health management frameworks.

MASLD prevalence exhibits significant heterogeneity across different populations and is influenced by factors such as age, sex, ethnicity, and comorbid conditions. In the Pakistani population, the overall MASLD prevalence was 14.8%, with higher rates observed in males (16.1%) than in females (13.4%) and a marked increase among individuals over 40 years of age (19.9%) relative to those under 40 years of age (8.7%).⁵ Within the Mediterranean region, the prevalence of MASLD among obese individuals has reached 40%, with a slightly higher rate in males (51.4%) than females (48.6%). Patients with MASLD also exhibited significantly elevated insulin resistance indices (HOMA-IR), diastolic blood pressure, body mass index (BMI), visceral fat area, and waist circumference compared to their non-MASLD counterparts.⁶

Certain populations demonstrate heightened susceptibility to MASLD. For instance, hemophilia has a prevalence rate as high as 47.2%, with overweight and obesity identified as independent risk factors.⁷ Similarly, individuals infected with HIV show comparably elevated MASLD prevalence, with visceral adiposity serving as a critical driver of disease progression.⁸ In the Italian primary care setting, MASLD prevalence stands at 9%, albeit with significant regional variation; among these patients, 25% have diabetes, 10% chronic kidney disease, 11% cardiovascular disease, and 28% obesity, indicating frequent multisystem complications.⁹ Additionally, MASLD prevalence among patients experiencing a first episode of acute ischemic stroke reaches 41%, peaking at 51.1% in individuals aged 50–59 years, suggesting the necessity for routine MASLD screening in cerebrovascular disease populations.¹⁰ Collectively, these data highlight the importance of tailored MASLD screening strategies targeting high-risk groups to enhance the early diagnostic efficiency.

The etiological factors contributing to MASLD are multifaceted and encompass metabolic, genetic, lifestyle, and environmental factors. Metabolic syndrome-related factors constitute the principal risk determinants. A prospective cohort study involving 11,245 MASLD patients identified diabetes, metabolic syndrome, and obesity as primary predictors of progression to hepatocellular carcinoma (HCC), with population attributable risk fractions (PAF) of 42.1%, 28.8%, and 13.2%, respectively.¹¹ Metabolic abnormalities substantially elevate the risk of MASLD, even in lean individuals. A study of 5,037 lean subjects (BMI < 24 kg/m²) developed a predictive model for MASLD, identifying alanine aminotransferase (ALT), total cholesterol, triglycerides, low-density lipoprotein cholesterol, creatinine, uric acid, and glycosylated hemoglobin as independent risk factors. The model demonstrated area under the curve (AUC) values of 0.870 and 0.887 in the training and validation cohorts, respectively.¹²

The influence of diet on MASLD pathogenesis warrants considerable attention. A prospective cohort study conducted in Tianjin, China, revealed a positive association between added sugar intake and MASLD risk, and individuals in the highest quartile of total added sugar consumption exhibited an 18% increased risk compared to those in the lowest quartile, with liquid added sugars conferring a greater risk than solid forms.¹³ Moreover, the relationship between gut microbiota dysbiosis and MASLD is being increasingly recognized. A meta-analysis of 25 studies encompassing 107,306 participants found that Helicobacter pylori infection was associated with elevated MASLD risk in both Asian and non-Asian populations.¹⁴ Collectively, these findings suggest that effective MASLD prevention necessitates a comprehensive approach that integrates metabolic risk factor management, dietary optimization, and modulation of gut microbiota homeostasis. (See Figure 1).

Figure 1.

Global Burden, High-Risk Groups, and Modifiable Drivers of MASLD: A Comprehensive Stratification and Management Approach.

Diagnosis

Imaging modalities, including ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and elastography, are the primary tools for diagnosing MASLD. However, ultrasonography is characterized by considerable subjectivity; a study involving 113 patients reported intra-observer agreement rates of 51% and inter-observer agreement rates ranging from 39% to 40%.¹⁵ Conversely, MRI-based proton density fat fraction (PDFF) measurements demonstrated superior accuracy. In a cohort of 37 patients with MASLD, PDFF values were significantly correlated with histological steatosis grades obtained via liver biopsy.¹⁶

Elastography is extensively used to evaluate fibrosis in MASLD. Acoustic radiation force impulse imaging (ARFI) has shown a diagnostic sensitivity of 80.2%, specificity of 85.2%, and area under the receiver operating characteristic curve (AUC) of 0.898 for detecting significant fibrosis (stage F ≥ 2).¹⁷ Magnetic resonance elastography (MRE) surpasses ARFI in diagnostic performance, with a meta-analysis reporting an AUC of 0.95 for cirrhosis detection.¹⁸ Additionally, controlled attenuation parameters (CAP), measured through transient elastography (TE), allow quantification of hepatic fat content. In patients with MASLD, CAP demonstrated a stronger correlation with steatosis grades determined by liver biopsy than with ultrasound.¹⁶ The integration of these imaging techniques enhances both the accuracy and comprehensiveness of MASLD diagnoses.

Biomarkers offer complementary noninvasive diagnostic avenues for MASLD, including serum proteins, metabolites, microRNAs, and products derived from the intestinal microbiota. The combined assessment of serum adiponectin, leptin, and insulin-like growth factor 1 (IGF-1) has demonstrated diagnostic utility; leptin yielded an area under the receiver operating characteristic curve (AUROC) of 0.83, whereas adiponectin combined with specific serum lipids achieved an AUROC of 0.80 for non-alcoholic steatohepatitis (NASH). Furthermore, IGF-1, in conjunction with the international normalized ratio (INR) versus ferritin, discriminated progressive fibrosis with an AUROC of 0.81.¹⁹ Metabolomic analyses have identified significant alterations in branched-chain amino acids, aromatic amino acids, and bile acids in the serum of MASLD patients, notably a reduction in glycine-conjugated bile acids correlating with disease severity.²⁰

Non-coding RNAs are promising biomarkers for MASLD diagnosis. For instance, serum levels of miR-122, miR-192, and miR-21 are markedly elevated in patients with MASLD and correlate with the extent of hepatic fibrosis.²¹ In a study involving HIV-infected individuals with MASLD, the AUROCs for Steato-ELSA, the fatty liver index (FLI), and the hepatic steatosis index (HSI) were 0.854, 0.840, and 0.805, respectively.²² Moreover, metabolites derived from the intestinal microbiota, such as lysine and histidine degradation products, are significantly increased in the feces of MASLD patients and may serve as disease biomarkers.²³ The combined use of these biomarkers is anticipated to enhance the accuracy and practicality of MASLD diagnosis.

Each noninvasive diagnostic modality presents distinct advantages and limitations, necessitating selection tailored to the clinical context. Ultrasonography is advantageous because of its low cost and widespread availability, but it exhibits limited sensitivity for detecting mild steatosis and is heavily dependent on operator expertise.¹⁵ CT is generally unsuitable for routine screening owing to its relatively low sensitivity to steatosis and the associated radiation exposure risks.²⁴ MRI-PDFF currently represents the most precise method for quantifying hepatic fat content; however, its high cost and limited accessibility limit its routine clinical use.¹⁶

Elastography techniques are particularly valuable for fibrosis assessment: ARFI offers moderate diagnostic accuracy for significant fibrosis, whereas MRE provides superior accuracy.^17,18 Indices such as FIB-4 and MASLD fibrosis score (NFS) exhibit high specificity but insufficient sensitivity for identifying progressive fibrosis.²² A study in MASLD patients demonstrated that combining shear wave measurement (SWM) with attenuation measurement (ATT) outperformed traditional transient elastography and CAP, with an AUROC of 0.951 for SWM in detecting progressive fibrosis.²⁵ These findings underscore that the selection of noninvasive diagnostic approaches should be based on a balance of diagnostic accuracy, cost-effectiveness, accessibility, and individual patient characteristics to optimize clinical outcomes. (Figure 2).

Figure 2.

Noninvasive Diagnostic Toolbox for MASLD: Imaging, Elastography, and Biomarkers. This diagram outlines a noninvasive diagnostic approach for MASLD using a combination of imaging modalities, elastography, and biomarkers. Imaging tools such as ultrasound, CT, and MRI-PDFF provide rapid and accurate assessment of liver fat content, with MRI-PDFF being the most reliable for fat quantification. Elastography techniques like TE/CAP, ARFI, and MRE assess liver stiffness, with MRE being particularly useful for detecting cirrhosis. Biomarkers from blood or multi-omics include adipokines (inflammation), IGF-1 (metabolic axis), miRNA (fibrosis link), and metabolites (bile acids), all of which aid in assessing disease progression and guiding clinical management. The combination of these tools enables efficient stratification of steatosis, NASH risk, and fibrosis stage.

Genetics

Considerable advances have been made in elucidating genetic susceptibility to MASLD, with multiple critical gene loci identified through genome-wide association studies (GWAS) and candidate gene analyses. A meta-analysis of GWAS utilizing electronic health records, encompassing 8,434 patients with MASLD and 770,180 controls, revealed five putative susceptibility loci proximal to the GCKR, TR1B1, MAU2/TM6SF2, APOE, and PNPLA3 genes.²⁶ Among these, the rs738409 locus (I148M variant) within the PNPLA3 gene has been the most extensively investigated genetic marker. The G allele at this locus is significantly associated with MASLD susceptibility, disease severity, and risk of progression to cirrhosis.²⁷

Emerging evidence has highlighted the involvement of noncoding RNAs in the pathogenesis of MASLD. For instance, the long non-coding RNA NEAT1 upregulates c-Jun and SREBP-1c expression, thereby promoting lipid accumulation in hepatocytes by sequestering miR-139-5p via a sponge mechanism.²⁸ Serum exosomal miRNA profiling has identified elevated levels of hsa-miR-122-5p, hsa-miR-146b-5p, and hsa-miR-197-3p in MASLD patients, correlating with disease severity.²⁹ Furthermore, CRISPR-based screening has implicated UGT1A9 as a pivotal regulator of bisphenol-induced mitochondrial dysfunction, with genetic variants potentially augmenting MASLD risk.³⁰ Collectively, these findings suggest that the interplay between coding and non-coding genetic elements constitutes a complex genetic architecture underlying MASLD and offers promising targets for precise diagnostic and therapeutic strategies.

Genetic variation not only influences MASLD susceptibility, but also significantly modulates disease progression and prognosis. Specifically, the PNPLA3 rs738409 G/G genotype is strongly associated with the prevalence of NASH among patients with MASLD, conferring a 2.27-fold increased risk of progression to advanced liver disease over long-term follow-up periods of up to 40 years.³¹ Additionally, the G allele of PNPLA3 correlates with more severe hepatic steatosis in individuals with Wilson’s disease, indicating a potential gene-environment interaction involving copper accumulation.³²

Other genetic variants have also been implicated in the pathogenesis of MASLD. The C771G polymorphism in the MLXIPL gene demonstrated a significant association with MASLD risk, with the C allele frequency being markedly higher in patients (68.30%) than in controls (51.59%).³³ The Q84R variant of the TRIB3 gene (Arg84 allele) elevates the risk of insulin resistance and MASLD by potentiating the inhibition of the insulin signaling pathway.³⁴ Moreover, the rs2235543 variant in the 11β-hydroxysteroid dehydrogenase 1 (HSD11B1) gene is associated with decreased MASLD risk among carriers of the minor allele (odds ratio = 0.46, 95% confidence interval: 0.23–0.93).³⁵ These studies underscore the role of genetic variation in modulating lipid metabolism, insulin signaling, and inflammatory pathways, thereby providing a foundation for individualized risk stratification.

The genetic architecture of familial MASLD is complex, encompassing both monogenic and polygenic interactions. Investigations of seven families revealed that monoallelic mutations in ABHD5 can cause autosomal dominant MASLD and dyslipidemia, exhibiting complete penetrance of the disease phenotype after 40 years of age.³⁶ Additionally, a rare variant of the MTTP gene (c.1691T > C, p.I564T) has been associated with familial MASLD, resulting in diminished microsomal triglyceride transfer protein activity and reduced apolipoprotein B secretion, thereby promoting hepatic lipid accumulation.³⁷

Polygenic inheritance patterns are predominant in familial MASLD cases. For example, the rs738409 variant in PNPLA3 is over-transmitted in MASLD pedigrees, implicating its contribution to familial aggregation.³⁸ A study of first-degree relatives of patients with MASLD in Italy reported an MASLD prevalence of 56.8%, with 14.4% exhibiting progressive fibrosis; diabetes mellitus emerged as an independent risk factor for fibrosis.³⁸ Furthermore, approximately 33% of lean MASLD patients harbor single-gene defects, such as homozygous pathogenic mutations in ALDOB (hereditary fructose intolerance) or heterozygous mutations in APOB (familial hypobetalipoproteinemia).³⁹ These findings indicate that the genetic etiology of familial MASLD is heterogeneous and that integrating single-gene mutation analysis with polygenic risk scoring may enhance the identification of individuals at elevated risk. (See Figure 3).

Figure 3.

Genetic Loci, Regulatory Layer, and Clinical Translation in MASLD. This diagram outlines the key genetic loci associated with MASLD, including PNPLA3 (rs738409), TM6SF2, GCKR, APOE, MLXIPL, and TRIB3. It highlights the regulatory layer, focusing on lncRNA-miRNA axes such as NEAT1 → miR-139-5p, as well as serum exosomal miRNAs and CRISPR-based functional screening. These genetic and regulatory factors play a crucial role in susceptibility stratification and progression prediction of MASLD, contributing to the identification of precision diagnosis and therapy targets for individualized management.

Pathophysiological Mechanisms of MASLD

Molecular Mechanism of Hepatic Steatosis

Hepatic steatosis represents the initial stage of MASLD, and its underlying molecular mechanisms are characterized by enhanced lipid synthesis, diminished fatty acid oxidation, and disrupted lipoprotein secretion. In the goose fatty liver model, progressive upregulation of the Fads1, Fads2, and Fads6 genes was observed, accompanied by a reduction in trans-C18:1n9 fatty acid levels, an inhibitor of Fads. This pattern suggests an increased compensatory capacity for long-chain polyunsaturated fatty acid (LC-PUFA) synthesis; however, this compensation remains insufficient to fully restore LC-PUFA depletion.⁴⁰ Furthermore, overexpression of AMPKα1 has been shown to mitigate lipid accumulation in hepatocytes by inhibiting the p38MAPK signaling pathway, downregulating the expression of lipogenic genes such as SREBP-1c and FAS, and upregulating genes involved in fatty acid oxidation, including CPT1A.⁴¹

Mitochondrial dysfunction is a critical contributor to steatosis development. In a murine model subjected to a high-fat, high-sugar diet, reduced hepatic levels of nicotinamide adenine dinucleotide (NAD+) were associated with decreased mitochondrial content and impaired function. Supplementation with nicotinamide riboside, a precursor of NAD+, enhances beta-oxidation and mitochondrial complex activity through the activation of SIRT1- and SIRT3-dependent mitochondrial unfolded protein responses, thereby reversing the MASLD phenotype.⁴² Endoplasmic reticulum (ER) stress interacts synergistically with oxidative stress to exacerbate steatosis progression. Exposure to bisphenolic compounds induces oxidative stress and cell death via UGT1A9-mediated disruption of mitochondrial calcium homeostasis.³⁰ Collectively, these findings indicate that hepatic steatosis arises from multifaceted pathway dysregulation and that therapeutic strategies targeting lipid metabolism, mitochondrial function, and cellular stress responses hold promise for the treatment of MASLD.

The Role of Inflammation in MASLD

The inflammatory response is a central mechanism that drives the progression of MASLD to NASH, involving the activation of both the innate and adaptive immune systems. In individuals diagnosed with metabolically associated fatty liver disease (MASLD), serum interleukin-6 (IL-6) concentrations are markedly elevated and exhibit a positive correlation with visceral adipose tissue volume, insulin resistance indices, and hepatic fat accumulation.⁴³ Dysbiosis of the intestinal microbiota further exacerbates hepatic inflammation via the “gut-liver axis.” Specifically, in obese pediatric patients with MASLD, overgrowth of Enterococcus faecalis strain B6 has been observed, whose metabolite tyramine activates the peroxisome proliferator-activated receptor gamma (PPAR-γ) pathway, thereby promoting lipid deposition and inflammatory processes.⁴⁴

The molecular mechanisms underlying localized hepatic inflammation are multifaceted. For instance, the Toll-like receptor 4 (TLR4) signaling pathway is activated in NASH patients, concomitant with elevated levels of its ligand lipopolysaccharide (LPS) and free fatty acids, which subsequently induce nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated secretion of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β).⁴⁵ Moreover, annexin A2 (ANXA2), a gene associated with ferroptosis, is upregulated in MASLD and contributes to disease progression by facilitating lipid peroxidation and inflammatory responses.⁴⁶ Experimental studies using murine models of MASLD have demonstrated that apigenin attenuates hepatic inflammation and lipid accumulation by inhibiting the sterol regulatory element-binding protein 1c/fatty acid synthase (SREBP1c/FASN) pathway and activation of autophagy mediated by AMP-activated protein kinase alpha (AMPKα), phosphoinositide 3-kinase (PI3K), Beclin1, and microtubule-associated protein 1 light chain 3 (LC3).⁴⁷ Collectively, these findings underscore the pivotal role of inflammation in MASLD pathogenesis and suggest that therapeutic strategies targeting inflammatory signaling pathways may effectively retard disease progression.

Relationship Between Insulin Resistance and MASLD

Insulin resistance is a fundamental pathological mechanism underlying both MASLD and metabolic syndrome, thereby establishing a deleterious feedback loop. In individuals with MASLD, hepatic insulin resistance is typified by enhanced gluconeogenesis and diminished glycogen synthesis, whereas insulin resistance in peripheral tissues leads to augmented lipolysis and increased transport of free fatty acids to the liver.⁴⁸ A study involving patients with type 2 diabetes mellitus (T2DM) and MASLD demonstrated significantly elevated serum levels of miR-17, miR-20a, miR-20b, and miR-122, with these miRNAs exhibiting superior diagnostic efficacy for MASLD compared to conventional serum biomarkers.⁴⁹

The molecular mechanisms driving insulin resistance encompass multiple signaling pathways. For instance, hepatocyte-specific knockdown of DDAH1 results in elevated serum concentrations of asymmetric dimethylarginine (ADMA), which exacerbates insulin resistance and hepatic steatosis by inhibiting nitric oxide synthesis and activating the NF-κB signaling pathway.⁵⁰ Additionally, upregulation of S100A6 promotes lipid accumulation and insulin resistance in hepatocytes through suppression of lipid phagocytosis.⁵¹ Furthermore, Ufmylation, a ubiquitin-like post-translational modification, stabilizes the UFBP1 protein, thereby mitigating ER stress and ameliorating insulin resistance and hepatic steatosis.⁵² Collectively, these findings indicate a reciprocal relationship between insulin resistance and MASLD, suggesting that therapeutic strategies targeting insulin signaling pathways and associated molecular modifications may offer novel avenues for the treatment of MASLD.

Effect of TCM on Pathological Mechanism of NFALD

TCM exerts multifaceted effects on the pathological mechanisms underlying MASLD. For instance, berberine has been demonstrated to activate the AMP-activated protein kinase (AMPK) pathway; treatment of MASLD rat models results in increased phosphorylation levels of AMPK in hepatic tissue, thereby inhibiting lipid synthesis.⁵³ Similarly, hawthorn leaf flavonoids have been reported to elevate serum adiponectin concentrations and stimulate the AdipoR2/AMPK signaling pathway.⁵⁴ Furthermore, certain TCM formulations, such as Qingzhi granules, modulate autophagic processes, as evidenced by an increased LC3-II/LC3-I ratio in the liver tissue of MASLD mice, which facilitates the degradation of lipid droplets.⁵⁵

In addition to these mechanisms, TCM significantly influences the gut microbiota composition. Administration of the Jianpi Shugan prescription in patients with MASLD was associated with an increased abundance of Bifidobacterium and a concomitant reduction in Enterobacteriaceae within the intestinal tract.⁵⁶ Correspondingly, animal studies have shown that Yinchen Wuling Powder enhances the prevalence of Akkermansia muciniphila in the intestines of MASLD mice and decreases serum LPS levels.⁵⁷ Moreover, TCM interventions can attenuate inflammatory pathways. For example, Chaishao Liujunzi Decoction has been found to reduce the expression of the NF-κB p65 subunit in the hepatic tissue of MASLD rat models.⁵⁸ (See Figure 4).

Figure 4.

MASLD Progression from Steatosis to NASH and Fibrosis: Mechanistic Overview. This diagram depicts the progression of MASLD from steatosis to NASH and ultimately fibrosis. The process begins with steatosis, characterized by increased de novo lipogenesis, impaired fatty acid oxidation, and lipid export dysregulation. This leads to mitochondrial and endoplasmic reticulum (ER) stress, which further exacerbates inflammation. Inflammation is primarily driven by gut-liver interactions, with dysbiosis triggering LPS release and TLR4 activation, culminating in NF-κB activation and increased cytokine production. Insulin resistance, manifesting as increased gluconeogenesis and lipolysis, leads to elevated free fatty acid (FFA) influx, perpetuating the vicious cycle and contributing to disease progression towards fibrosis.

Notes: ↑ indicates enhancement of the indicated pathological process or molecular response, including increased de novo lipogenesis, pro-inflammatory cytokine production, hepatic gluconeogenesis, and peripheral lipolysis. ↓ indicates impairment or suppression of the indicated metabolic process, including reduced fatty acid oxidation and glycogen synthesis. Increased lipolysis consequently enhances free fatty acid (FFA) delivery to the liver, reinforcing hepatic steatosis and insulin resistance.

Modern Medical Treatment

Therapeutic targets for MASLD are progressively broadening, encompassing pathways involved in lipid metabolism, inflammatory processes, insulin signaling, and gut microbiota modulation. For instance, fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, has been shown to reduce hepatic lipid accumulation and inflammation by enhancing fatty acid oxidation pathways.⁵⁹ Similarly, liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, significantly ameliorated dyslipidemia and insulin resistance in MASLD murine models by downregulating lysophosphatidylcholine, phosphatidylcholine, and triglyceride concentrations while upregulating L-isoleucine levels.⁶⁰ Resmetirom, a THR-β agonist, represents one of the most important breakthroughs among newly developed Western pharmacotherapies; it improves hepatic steatosis and fibrosis via thyroid hormone-mediated metabolic regulation, yet it is limited by adverse reactions and restricted real-world accessibility. In contrast, TCM interventions provide multi-target regulation covering lipid metabolism, gut-liver axis homeostasis and inflammatory response, yet such theoretical advantages still need to be confirmed by high-quality clinical trials.

Recent studies have identified several novel pharmacological targets. For example, obeticholic acid, a farnesoid X receptor (FXR) agonist, mitigates liver fibrosis in patients with NASH by modulating bile acid metabolism and inflammatory responses.⁵⁹ Additionally, the sodium-glucose cotransporter 2 (SGLT2) inhibitor engliflozin decreases hepatic lipid deposition and inflammation by promoting glucosuria.⁶⁰ In a MASLD mouse model, Huanglian Jiedu Decoction was found to improve insulin resistance and hepatic inflammation via activation of the Sirtuin 1 (Sirt1)/NF-κB signaling pathway and suppression of genes associated with lipid synthesis.⁶¹ The clinical translation of these agents holds promise for expanding the therapeutic options for MASLD management.

Lifestyle modification remains the cornerstone of MASLD treatment, incorporating dietary adjustments, physical activity, and behavioral interventions. A culturally tailored 10-week lifestyle program in Latin American individuals with prediabetes type 2 mellitus (pre-T2DM) resulted in significant reductions in fasting glucose levels, with women exhibiting more pronounced improvements in weight, BMI, waist-to-hip ratio, and body fat percentage.⁶² Both aerobic and resistance training have been shown to reduce hepatic fat content, with aerobic exercise demonstrating superior efficacy.⁶³

Behavioral strategies and digital health technologies enhance adherence to lifestyle modifications. For example, smartphone applications and wearable devices facilitate effective monitoring of dietary intake and physical activity, thereby improving patient self-management.⁶⁴ In an elderly population at cardiovascular risk, the use of mobile health (mHealth) tools, such as the MyFitnessPal application combined with activity trackers over 12 weeks, led to significant improvements in health behaviors and increased user satisfaction.⁶⁴ Tailoring these lifestyle interventions to individual patient needs is anticipated to optimize therapeutic outcomes and retard MASLD progression.

Surgical interventions are primarily reserved for MASLD patients with severe obesity and include bariatric procedures and liver transplantations. Bariatric surgeries, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), have been shown to markedly reduce hepatic steatosis and inflammation. A meta-analysis revealed significant improvements in steatosis, hepatocyte ballooning, lobular inflammation, and fibrosis following bariatric surgery in MASLD patients.⁶⁵ Furthermore, these procedures improve the metabolic parameters associated with MASLD, including insulin resistance, dyslipidemia, and hypertension.⁶⁶

Liver transplantation remains the definitive treatment for end-stage MASLD. A study involving patients with NASH-related cirrhosis reported a five-year post-transplant survival rate comparable to that of cirrhosis from other etiologies; however, these patients exhibited an elevated risk of cardiovascular complications.⁶⁷ Moreover, patients with MASLD are predisposed to disease recurrence post-transplantation, necessitating rigorous postoperative metabolic management.⁶⁸ Collectively, these findings underscore the critical role of surgical interventions in MASLD treatment while emphasizing the importance of stringent patient selection, perioperative care, and long-term follow-up.

Basic Theory of Comprehensive Treatment of NFALD with Chinese Medicine

MASLD is classified within TCM under categories such as “hypochondriac pain,” “accumulation,” and “phlegm turbidity.” Its fundamental pathogenesis is characterized by a dual pattern of “deficiency at the root and excess in the superficial aspects.” The deficiency primarily pertains to spleen insufficiency, whereas excess involves pathological factors including phlegm dampness, qi stagnation, and blood stasis.⁶⁹ A cross-sectional investigation involving 1,677 participants demonstrated a significant association between a phlegm-dampness constitution and increased MASLD risk, independent of BMI, diabetes, and other confounding variables.⁷⁰ Intestinal dysbiosis is regarded as a critical intermediary linking TCM constitutional types and MASLD. Specifically, children with MASLD exhibit markedly reduced gut microbial diversity, characterized by diminished Bacteroides abundance and elevated Prevotella levels.⁷¹ Further research identified that alterations in gut microbiota among MASLD patients presenting with damp-heat syndrome, such as decreased Agathobacter abundance, were negatively correlated with serum total bile acid concentrations.⁷²

The TCM concept of “liver-spleen correlation” is particularly salient in the pathogenesis of MASLD. The liver is responsible for the smooth circulation of qi, whereas the spleen governs the transportation, transformation, and distribution of nutrients derived from food and water. Disruptions such as liver-qi stagnation due to emotional disturbances or spleen-qi deficiency resulting from dietary irregularities can precipitate water retention, dampness accumulation, and endogenous phlegm formation, culminating in fatty liver development.⁷³ Experimental models have revealed that MASLD rats exhibiting liver depression and spleen deficiency show decreased hepatic expression of PPARγ protein, alongside increased fatty acid synthase (FASN) expression.⁷⁴ Moreover, intestinal barrier dysfunction is a pivotal factor in MASLD progression; for instance, zonula occludens-1 (ZO-1) expression is reduced in the colonic tissue of MASLD mice, a deficit that can be ameliorated by inhibiting the RhoA/ROCK signaling pathway.⁷⁵

Therapeutic approaches in TCM for MASLD adhere to the principle of “syndrome differentiation and treatment,” emphasizing the restoration of liver and spleen function and regulation of qi, blood, and body fluid metabolism. Grounded in the theory of “phlegm retention,” herbal agents that eliminate dampness and resolve phlegm—such as Alisma orientale and Poria cocos—are extensively utilized. Network pharmacology analyses have identified 23-acetyl alisol B, an active constituent of Alisma orientale, targeting HMGCR and PTPN1 to ameliorate MASLD via modulation of lipid metabolic pathways.⁷⁶ Additionally, Huangqin Huanglian Decoction, a formulation aimed at clearing heat and removing dampness, has been shown to reduce serum triglyceride levels in MASLD murine models, with its mechanism linked to activation of the PPARα pathway.⁷⁷

The central therapeutic strategy for MASLD in TCM involves “soothing the liver and invigorating the spleen.” Chaihu Shugan Powder exerts its effects by modulating the nuclear receptors PPARγ and FXR. Clinical evidence indicates that this formulation can decrease serum ALT levels in patients with MASLD and upregulate hepatic PPARγ mRNA expression.⁷⁸ Herbs that invigorate the spleen and replenish qi, such as Astragalus membranaceus and Atractylodes macrocephala, contribute to improving insulin resistance. A meta-analysis of 1,335 patients reported that combining spleen-invigorating formulas with conventional Western medicine achieved an overall efficacy rate of 89.8%, significantly surpassing that of Western medicine alone.⁷⁹ Furthermore, based on the “intestinal microbiota-metabolic axis” theory, TCM compounds such as Sijunzi Decoction can modulate gut microbiota composition, increasing the abundance of short-chain fatty acid-producing bacteria (eg, Roseburia) by approximately 2.1-fold, thereby enhancing hepatic lipid metabolism.⁵⁶

TCM compounds exert therapeutic effects on MASLD through multicomponent and multitarget synergistic mechanisms. For example, Qingzhi granules contain bioactive constituents, such as curcumin and berberine, which activate autophagy pathways. In vitro studies demonstrated that treatment with Qingzhi granules increased the LC3-II/LC3-I ratio and decreased mTOR phosphorylation in HepG2 cells. Another formulation, the Chaishao Liujunzi Decoction, exhibits anti-inflammatory properties by inhibiting the p38 MAPK/NF-κB signaling pathway, resulting in reduced hepatic expression of TNF-α mRNA and IL-6 levels in MASLD rat models.⁵⁸

Modulation of intestinal microbiota represents a significant mechanism underlying TCM efficacy of TCM. Yinchen Wuling Powder notably increased the abundance of Akkermansia muciniphila in the intestines of MASLD mice and concomitantly decreased serum LPS levels.⁵⁷ Additionally, TCM compounds influence bile acid metabolism; for instance, Huangqin Huanglian Decoction upregulates hepatic FXR expression in MASLD mice, promoting bile acid synthesis.⁷⁷ Metabolomic analyses further revealed that Qingzhi granules regulate serum phospholipid metabolism in MASLD patients, characterized by a 1.8-fold increase in phosphatidylcholine levels and a 0.6-fold decrease in sphingomyelin concentrations.⁸⁰ It should be noted that reference⁸⁰ corresponds to an ongoing randomized controlled trial protocol rather than published completed clinical outcome data. (See Figure 5).

Figure 5.

Modern Medicine vs TCM Comprehensive Therapy for MASLD: Shared Outcomes. This diagram compares two therapeutic approaches for MASLD: modern medicine and Traditional Chinese Medicine (TCM). In modern medicine, treatment begins with lifestyle modification (diet, physical activity, and behavioral support), followed by digital adherence using apps and wearables, targeted pharmacotherapy (eg, PPARα, GLP-1RA, FXR, and SGLT2 inhibitors), and, in severe cases, surgery or organ transplant. In TCM, the approach involves syndrome differentiation based on the concepts of root deficiency and branch excess, alongside liver-spleen correlation. Treatment involves herbal formulas, active compounds such as berberine and flavonoids, and external therapies like acupuncture and moxibustion. Both approaches aim to achieve shared outcomes, including the reduction of liver fat, improvement in metabolic profiles, and lowering of fibrosis risk.

Notes: ↓ for liver fat denotes a reduction in intrahepatic lipid accumulation and steatosis, whereas ↓ for fibrosis risk denotes a lower likelihood or severity of fibrosis progression. “Improved metabolic profile” refers to an overall improvement in metabolic homeostasis, including better insulin sensitivity, glycemic control, and lipid metabolism, rather than a uniform increase in individual metabolic biomarkers.

Clinical Practice of TCM in the Treatment of NFALD

A wealth of clinical evidence has been accumulated for single Chinese herbs, compound prescriptions, acupuncture, moxibustion, acupoint catgut embedding, tuina and other TCM therapies. These interventions exert definite curative effects in improving liver function, blood lipids, hepatic fat deposition, insulin resistance and intestinal microecology, though many clinical investigations suffer from small sample sizes, heterogeneity in syndrome differentiation and overall low methodological quality of relevant systematic reviews. Berberine can reduce serum alanine transaminase (ALT) levels in patients with MASLD.⁵³ A meta-analysis including 800 participants demonstrated that Salvia miltiorrhiza can elevate the liver-spleen CT ratio of MASLD patients.⁸¹ Furthermore, hawthorn leaf flavonoids are effective in lowering serum triglyceride (TG) levels.⁵⁴ Following the principle of treatment based on syndrome differentiation, TCM compound prescriptions act via multiple active ingredients and targets, serving as the mainstream regimen for MASLD treatment. Chai Shao Liu Jun Zi Tang can decrease serum ALT levels and upregulate the expression of peroxisome proliferator-activated receptor γ (PPARγ) in liver tissues, thereby exerting combined anti-inflammatory and metabolic regulatory effects.⁷⁸ A meta-analysis of 1335 patients revealed that spleen-strengthening compound prescriptions characterized by soothing the liver, invigorating the spleen, eliminating dampness and resolving phlegm achieved a total effective rate of 89.8% when combined with Western medicine, which was significantly superior to Western medicine alone.⁷⁹ Qingzhi Granules can directly reduce hepatic fat accumulation and improve multiple liver function indicators, and are widely applied in MASLD patients with lipid metabolism disorders.⁸⁰

The mechanism of action of acupuncture in treating MASLD appears to involve modulation of metabolic pathways. A meta-analysis of 1,349 patients demonstrated that acupoint catgut embedding achieved an overall effective rate of 89.8%, which was significantly higher than that observed in Western medicine groups.⁸² Experimental studies in MASLD rat models have shown that electroacupuncture at Zusanli (ST 36) and Sanyinjiao (SP 6) reduces serum TG levels, potentially through activation of the AMP-AMPK pathway.⁸³ Moreover, massage therapy has been associated with improvements in insulin resistance among MASLD patients, as evidenced by a reduction in the homeostasis model assessment of insulin resistance (HOMA-IR) index.⁸⁴

The therapeutic effects of moxibustion in MASLD are linked to modulation of the gut microbiota. Animal studies have demonstrated that moxibustion increases the abundance of Bifidobacterium in the intestines of MASLD mice and decreases the serum LPS levels.⁵⁶ Additionally, ear acupoint bean pressing has been reported to reduce serum ALT levels in patients with MASLD.⁸⁴

The evaluation of TCM efficacy in MASLD treatment should integrate both clinical biomarkers and histopathological changes. The aforementioned meta-analysis involving 1,335 patients confirmed that Jianpi Fang combined with Western medicine significantly improved treatment outcomes compared with Western medicine alone.⁷⁹ Qingzhi granules have also been shown to decrease hepatic fat content and enhance liver function parameters in MASLD patients.⁸⁰

The long-term benefits of TCM in the management of MASLD are substantial. A cohort study including 13,072 patients indicated that TCM interventions reduced the incidence of cirrhosis in individuals with MASLD.⁸⁵ Furthermore, Chinese herbal compounds have been found to favorably alter intestinal microbiota composition, increasing Bacteroides abundance while decreasing Firmicutes abundance following treatment.⁵⁶

Two Chinese randomized controlled trials (RCTs) published in 2025 were included in this study, focusing on TCM compound prescriptions and combined interventions of lifestyle modification plus traditional Chinese medicine. Table 1 explicitly distinguishes completed trial results from study protocols; entries based on study protocols are specially labelled and should not be interpreted as finished clinical evidence. The table below summarizes the sample size, intervention protocols, intervention duration and primary outcome indicators of each study, with the GRADE evidence quality level listed accordingly. (See Table 1)

Table 1.

Summary of Included Clinical Studies on TCM for MASLD

Reference	Study Type	Sample Size	Intervention	Control	Duration	Primary Outcomes	GRADE Quality
[79]	Completed Multicenter Meta-analysis	1335 participants	Spleen-invigorating TCM formulas combined with conventional Western medicine	Single conventional Western medicine treatment	Individualized according to included trials	Significantly improved liver function, reduced hepatic steatosis, and achieved an overall clinical effective rate of 89.8%, superior to Western medicine monotherapy	Moderate
[80]	Ongoing RCT Protocol (No finalized outcomes)	Planned enrollment: unreported	Jiu Wei Qingzhi formula combined with routine intervention	Single routine clinical intervention	Planned trial duration	Trial designed to assess improvements in lipid metabolism, liver function and serum metabolomic characteristics (no published clinical results available)	Not applicable (Protocol)
[82]	Completed Meta-analysis	1349 participants	Acupoint catgut embedding therapy combined with routine intervention	Western medicine conventional treatment	Individualized according to included trials	Acupuncture-related TCM intervention significantly reduced transaminase levels and improved hepatic fat deposition, with an overall effective rate of 89.8%	Moderate
[56]	Completed Clinical Observation	Relevant MASLD patients	Jianpi Shugan prescription TCM intervention	Conventional symptomatic treatment	12 weeks	TCM intervention optimized intestinal flora structure, increased beneficial Bifidobacterium abundance, and improved metabolic disorders in MASLD patients	Low-Moderate

Notes: Studies are classified into completed randomized controlled trials and study protocols. Study protocols represent planned trials without published final outcome data and are marked with “Protocol” label, which cannot be equated with completed clinical evidence. GRADE evidence quality is provided for each entry.

Controversies and Future Prospects of TCM in the Treatment of MASLD

Debates over TCM for MASLD mainly focus on standardization and mechanistic research. Complex TCM formulations lack universal quality standards; saikosaponin content in Chaihu Shugan Powder differed three times among manufacturers.⁷⁸ Most relevant studies are confined to phenomenological observations without in-depth molecular exploration,⁸⁶ and an analysis of seven systematic reviews showed only one achieved moderate methodological quality.⁸⁶ When comparing therapeutic strategies, it should be noted that newly emerging Western single-target agents such as THR-β agonists have shown encouraging phase III results, while TCM multi-target advantages remain largely theoretical and await robust international multicenter validation.

Future studies should combine precision medicine and multiomics technologies. Personalized TCM based on gut microbiota can improve clinical efficacy.⁵⁶ Integrated transcriptomic and metabolomic analyses have proven that Qingzhi granules regulate 222 hepatic genes in MASLD patients.⁸⁷

To advance TCM internationalization, unified global quality criteria must be established. The international standard of Huangqin Huanglian Tang has been adopted by the WHO.⁷⁷ High-quality multinational multicenter trials are also required: Jianpi Fang combined with Western medicine yielded an overall effective rate of 89.8% in a 1,335-patient international study.⁷⁹ Additionally, popularizing TCM helps gain global recognition, and acupuncture for MASLD has been included in NIH clinical guidelines.⁸²

Disclosure

The authors declare that they have no affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript.