Interleukin-mediated therapies in liver diseases and comorbidity effects

Cytokines like interleukins(ILs)play important roles in inflammation and innate immune.Yang and Zhang carried out an interesting study related to ILs and hepatic diseases.They described the role of ILs in the pathogenesis and resolution of hepatic disorders.The authors summarized alcohol-related liver disease and virus-induced hepatitis,as far as clinical studies a fortiori carried out on ILmediated treatments pertaining to these dysfunctions.This editorial contributes to the review by Yang and Zhang titled,"Interleukins in liver disease treatment",and focuses on therapies mediated by ILs in comorbid liver diseases.The documentary search was conducted on recent pertinent literature,primarily using the Google Scholar and PubMed databases.

Ferritinophagy: A new idea for liver diseases regulated by ferroptosis

Background:The discovery of regulatory cell death has led to a breakthrough in the therapeutic field.Various forms of cell death,such as necrosis,apoptosis,pyroptosis,autophagy,and ferroptosis,play an important role in the development of liver diseases.In general,more than one form of cell death pathways is responsible for the disease state.Therefore,it is particularly important to study the regulation and interaction of various cell death forms in liver diseases.Data sources:We performed a PubMed search up to November 2022 with the following keywords:ferritinophagy,ferroptosis,and liver disease.We also used terms such as signal path,inducer,and inhibitor to supplement the query results.Results:This review summarized the basic characteristics of ferritinophagy and ferroptosis and the regulation of ferroptosis by ferritinophagy and reviewed the key targets and treatment strategies of ferroptosis in different liver diseases.Conclusions:Ferritinophagy is a potential therapeutic target in ferroptosis-related liver diseases.

Immune remodulation in pediatric inherited metabolic liver diseases

Inherited metabolic liver diseases arise from genetic mutations that lead to dis-ruptions in liver metabolic pathways and are predominantly observed in pedia-tric populations.The spectrum of genetic metabolic liver disorders is diverse,encompassing a range of conditions associated with aberrations in iron,copper,carbohydrate,lipid,protein,and amino acid metabolism.Historically,research in the domain of genetic metabolic liver diseases has predominantly concentrated on hepatic parenchymal cell alterations.Nevertheless,emerging studies suggest that inherited metabolic liver diseases exert significant influences on the immune microenvironment,both within the liver and systemically.This review endeavors to encapsulate the immunological features of genetic metabolic liver diseases,aiming to expand the horizons of researchers in this discipline,and to elucidate the underlying pathophysiological mechanisms pertinent to hereditary metabolic liver diseases and to propose innovative therapeutic approaches.

Ferroptosis in liver diseases:Fundamental mechanism and clinical implications

This editorial discusses a recently published paper in the World Journal of Gastroenterology.Our research focuses on p53's regulatory mechanism for controlling ferroptosis,as well as the intricate connection between ferroptosis and liver diseases.Ferroptosis is a specific form of programmed cell death that is dependent on iron and displays unique features in terms of morphology,biology,and genetics,distinguishing it from other forms of cell death.Ferroptosis can affect the liver,which is a crucial organ responsible for iron storage and metabolism.Mounting evidence indicates a robust correlation between ferroptosis and the advancement of liver disorders.P53 has a dual effect on ferroptosis through various distinct signaling pathways.However,additional investigations are required to clarify the regulatory function of p53 metabolic targets in this complex association with ferroptosis.In the future,researchers should clarify the mechanisms by which ferroptosis and other forms of programmed cell death contribute to the progression of liver diseases.Identifying and controlling important regulatory factors associated with ferroptosis present a promising therapeutic strategy for liver disorders.

Impact of metabolic dysfunction-associated steatotic liver disease on the efficacy of immunotherapy in patients with chronic hepatitis B-related hepatocellular carcinoma

Objective:To investigate the impact of metabolic dysfunction-associated steatotic liver disease(MASLD)on the efficacy of immune checkpoint inhibitor(ICI)-based therapy in patients with chronic hepatitis B(CHB)-related hepatocellular carcinoma(HCC).Methods:A total of 155 patients with CHB-related HCC who received ICI–based therapy(in the Department of Hepatology,Tianjin Second People’s Hospital and Department of Hepatobiliary Oncology,Tianjin Medical University Cancer Institute&Hospital)between April 2021 and December 2023 were evaluated.Patients were divided into two groups:MASLD concurrent with CHB[MASLD-CHB](n=38),and CHB(n=117).Results:The median progression-free survival(PFS,6.9 months vs.9.3 months;P=0.001),progressive disease(57.89%vs.37.61%;P=0.028),and disease control rate(42.11%vs.62.39%;P=0.028)in the MASLD-CHB group were significantly worse than the CHB group.The median overall survival was not attained.The percentage of CD4+PD1+(17.56%vs.8.89%;P<0.001)and CD8+PD1+T cells(10.50%vs.7.42%;P=0.005)in patient samples from the MASLD-CHB group were significantly higher than the CHB group.Concurrent MASLD[hazard ratio(HR)=1.921;95%CI,1.138–3.245;P=0.015]and alpha-fetoprotein levels after 3 months of treatment(HR=2.412;95%CI,1.360–4.279;P=0.003)were independent risk factors for PFS in all patients.Conclusions:ICI-based therapy in patients with CHB-related HCC and concurrent MASLD resulted in poorer efficacy and shorter PFS compared to patients with CHB-related HCC alone.

Characterization of acute-on-chronic liver diseases: A multicenter prospective cohort study

BACKGROUND Acute-on-chronic liver disease(AoCLD)accounts for the majority of patients hospitalized in the Department of Hepatology or Infectious Diseases.AIM To explore the characterization of AoCLD to provide theoretical guidance for the accurate diagnosis and prognosis of AoCLD.METHODS Patients with AoCLD from the Chinese Acute-on-Chronic Liver Failure(ACLF)study cohort were included in this study.The clinical characteristics and outcomes,and the 90-d survival rate associated with each clinical type of AoCLD were analyzed,using the Kaplan-Meier method and the log-rank test.RESULTS A total of 3375 patients with AoCLD were enrolled,including 1679(49.7%)patients with liver cirrhosis acute decompensation(LC-AD),850(25.2%)patients with ACLF,577(17.1%)patients with chronic hepatitis acute exacer-bation(CHAE),and 269(8.0%)patients with liver cirrhosis active phase(LC-A).The most common cause of chronic liver disease(CLD)was HBV infection(71.4%).The most common precipitants of AoCLD was bacterial infection(22.8%).The 90-d mortality rates of each clinical subtype of AoCLD were 43.4%(232/535)for type-C ACLF,36.0%(36/100)for type-B ACLF,27.0%(58/215)for type-A ACLF,9.0%(151/1679)for LC-AD,3.0%(8/269)for LC-A,and 1.2%(7/577)for CHAE.CONCLUSION HBV infection is the main cause of CLD,and bacterial infection is the main precipitant of AoCLD.The most common clinical type of AoCLD is LC-AD.Early diagnosis and timely intervention are needed to reduce the mortality of patients with LC-AD or ACLF.

Dynamic changes and clinical value of lipocalin 2 in liver diseases caused by microbial infections

Lipocalin 2(LCN2)plays a pivotal role in iron metabolism,particularly in the context of microbial infection resistance(e.g.,viruses,bacteria,parasites,etc.).LCN2 combats microbial infection by directly assisting the body in competing with microorganisms for iron,inducing immune cells to secrete various cytokines to enhance systemic immune responses,or recruiting neutrophils to infectious sites.The liver serves as the primary organ for LCN2 secretion during microbial infections.This review encapsulates recent advances in dynamic changes,clinical values,and the effects of LCN2 in infectious liver diseases caused by various microbial microorganisms.

Overview of emerging therapies for demyelinating diseases

This paper provides an overview of autoimmune disorders of the central nervous system,specifically those caused by demyelination.We explore new research regarding potential therapeutic interventions,particularly those aimed at inducing remyelination.Remyelination is a detailed process,involving many cell types–oligodendrocyte precursor cells(OPCs),astrocytes,and microglia–and both the innate and adaptive immune systems.Our discussion of this process includes the differentiation potential of neural stem cells,the function of adult OPCs,and the impact of molecular mediators on myelin repair.Emerging therapies are also explored,with mechanisms of action including the induction of OPC differentiation,the transplantation of mesenchymal stem cells,and the use of molecular mediators.Further,we discuss current medical advancements in relation to many myelin-related disorders,including multiple sclerosis,optic neuritis,neuromyelitis optica spectrum disorder,myelin oligodendrocyte glycoprotein antibodyassociated disease,transverse myelitis,and acute disseminated encephalomyelitis.Beyond these emerging systemic therapies,we also introduce the dimethyl fumarate/silk fibroin nerve conduit and its potential role in the treatment of peripheral nerve injuries.Despite these aforementioned scientific advancements,this paper maintains the need for ongoing research to deepen our understanding of demyelinating diseases and advance therapeutic strategies that enhance affected patients’quality of life.

Interplay of gut microbiota,glucagon-like peptide receptor agonists,and nutrition:New frontiers in metabolic dysfunction-associated steatotic liver disease therapy

The gut-liver axis plays a crucial role in the development and progression of metabolic dysfunction-associated steatotic liver disease(MASLD).Key metabolites,including lipopolysaccharides,short-chain fatty acids(SCFAs),bile acids,and beneficial gut bacteria such as Bifidobacterium and Lactobacillus,are pivotal in this process.Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)show promise in managing MASLD by promoting weight loss,enhancing insulin secretion,and improving liver health.They restore gut-liver axis functionality,and their effects are amplified through dietary modifications and gut microbiometargeted therapies.Emerging research highlights the interplay between GLP-1 RAs and gut microbiota,indicating that the gut microbiome significantly influences therapeutic outcomes.Metabolites produced by gut bacteria,can stimulate glucagon-like peptide-1(GLP-1)secretion,further improving metabolic health.Integrating dietary interventions with GLP-1 RA treatment may enhance liver health by modulating the gut microbiota-SCFAs-GLP-1 pathway.Future research is needed to understand personalized effects,with prebiotics and probiotics offering treatment avenues for MASLD.

Non-alcoholic fatty liver disease in type 2 diabetes:Emerging evidence of benefit of peroxisome proliferator-activated receptors agonists and incretin-based therapies

Nonalcoholic fatty liver disease(NAFLD)is a global epidemic,affecting more than half of the people living with type 2 diabetes(T2D).The relationship between NAFLD and T2D is bidirectional and the presence of one perpetuates the other,which significantly increases the hepatic as well as extrahepatic complications.Until recently,there was no approved pharmacological treatment for NAFLD/nonalcoholic steatohepatitits(NASH).However,there is evidence that drugs used for diabetes may have beneficial effects on NAFLD.Insulin sensitizers acting through peroxisome proliferator-activated receptor(PPAR)modulation act on multiple levels of NAFLD pathogenesis.Pioglitazone(PPARγ agonist)and saroglitazar(PPARα/γagonist)are particularly beneficial and recommended by several authoritative bodies for treating NAFLD in T2D,although data on biopsyproven NASH are lacking with the latter.Initial data on elafibanor(PPARα/δ agonist)and Lanifibranor(pan PPAR agonist)are promising.On the other hand,incretin therapies based on glucagon-like peptide-1(GLP-1)receptor agonists(GLP-1RA)and dual-and triple-hormone receptor co-agonists reported impressive weight loss and may have anti-inflammatory and antifibrotic properties.GLP-1 RAs have shown beneficial effects on NAFLD/NASH and more studies on potential direct effects on liver function by dual-and triple-agonists are required.Furthermore,the long-term safety of these therapies in NAFLD needs to be established.Collaborative efforts among healthcare providers such as primary care doctors,hepatologists,and endocrinologists are warranted for selecting patients for the best possible management of NAFLD in T2D.

Insights of gut-liver axis in hepatic diseases:Mechanisms,clinical implications,and therapeutic potentials

With the rising prevalence of chronic liver diseases worldwide,there exists a need to diversify our artillery to incorporate a plethora of diagnostic and therapeutic methods to combat this disease.Currently,the most common causes of liver disease are non-alcoholic fatty liver disease,hepatitis,and alcoholic liver disease.Some of these chronic diseases have the potential to transform into hepatocellular carcinoma with advancing fibrosis.In this review,we analyse the relationship between the gut and liver and their significance in liver disease.This two-way relationship has interesting effects on each other in liver diseases.The gut microbiota,through its metabolites,influences the metabolism in numerous ways.Careful manipulation of its composition can lead to the discovery of numerous therapeutic potentials that can be applied in the treatment of various liver diseases.Numerous cohort studies with a pan-omics approach are required to understand the association between the gut microbiome and hepatic disease progression through which we can identify effective ways to deal with this issue.

Team players in the pathogenesis of metabolic dysfunctionsassociated steatotic liver disease:The basis of development of pharmacotherapy

Nutrient metabolism is regulated by several factors.Social determinants of health with or without genetics are the primary regulator of metabolism,and an unhealthy lifestyle affects all modulators and mediators,leading to the adaptation and finally to the exhaustion of cellular functions.Hepatic steatosis is defined by presence of fat in more than 5%of hepatocytes.In hepatocytes,fat is stored as triglycerides in lipid droplet.Hepatic steatosis results from a combination of multiple intracellular processes.In a healthy individual nutrient metabolism is regulated at several steps.It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component.Several hormones,peptides,and genes have been described that participate in nutrient metabolism.Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP.As of now several publications have revealed very intricate regulation of nutrient metabolism,where most of the regulatory factors are tied to each other bidirectionally,making it difficult to comprehend chronological sequence of events.Insulin hormone is the primary regulator of all nutrients’metabolism both in prandial and fasting states.Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes;metabolic,inflammation and repair,and cell growth and regeneration.Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands,adiponectin,leptin,and adiponutrin.Insulin hormone has direct effect on these final modulators.Whereas blood glucose level,serum lipids,incretin hormones,bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle.The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease(MASLD)that help us understand the disease natural course,risk stratification,role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine.PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states;MASLD,cardiovascular disease and cancer.More than 1000 publications including original research and review papers were reviewed.

Antioxidant and anti-inflammatory agents in chronic liver diseases:Molecular mechanisms and therapy

Chronic liver disease(CLD)is a continuous process that causes a reduction of liver function lasting more than six months.CLD includes alcoholic liver disease(ALD),non-alcoholic fatty liver disease(NAFLD),chronic viral infection,and autoimmune hepatitis,which can lead to liver fibrosis,cirrhosis,and cancer.Liver inflammation and oxidative stress are commonly associated with the development and progression of CLD.Molecular signaling pathways such as AMPactivated protein kinase(AMPK),C-Jun N-terminal kinase,and peroxisome proliferator-activated receptors(PPARs)are implicated in the pathogenesis of CLD.Therefore,antioxidant and anti-inflammatory agents from natural products are new potent therapies for ALD,NAFLD,and hepatocellular carcinoma(HCC).In this review,we summarize some powerful products that can be potential applied in all the stages of CLD,from ALD/NAFLD to HCC.The selected agents such asβ-sitosterol,curcumin,genistein,and silymarin can regulate the activation of several important molecules,including AMPK,Farnesoid X receptor,nuclear factor erythroid 2-related factor-2,PPARs,phosphatidylinositol-3-kinase,and lysyl oxidase-like proteins.In addition,clinical trials are undergoing to evaluate their efficacy and safety.

Muscle strength and non-alcoholic fatty liver disease/metabolicassociated fatty liver disease

This editorial comments on an article published in a recent issue of World Journal of Gastroenterology,entitled“Association of low muscle strength with metabolic dysfunction-associated fatty liver disease:A nationwide study”.We focused on the association between muscle strength and the incidence of non-alcoholic fatty liver disease(NAFLD)and metabolic-associated fatty liver disease(MAFLD),as well as the mechanisms underlying the correlation and related clinical applications.NAFLD,which is now redefined as MAFLD,is one of the most common chronic liver diseases globally with an increasing prevalence and is characterized by malnutrition,which may contribute to decreased muscle strength.Reduction of muscle strength reportedly has a pathogenesis similar to that of NAFLD/MAFLD,including insulin resistance,inflammation,sedentary behavior,as well as insufficient vitamin D.Multiple studies have focused on the relationship between sarcopenia or muscle strength and NAFLD.However,studies investigating the relationship between muscle strength and MAFLD are limited.Owing to the shortage of specific medications for NAFLD/MAFLD treatment,early detection is essential.Furthermore,the relationship between muscle strength and NAFLD/MAFLD suggests that improvements in muscle strength may have an impact on disease prevention and may provide novel insights into treatments including dietary therapy,as well as tailored physical activity.

Glucagon-like peptide 1 agonists are potentially useful drugs for treating metabolic dysfunction-associated steatotic liver disease

In this editorial,we comment on Yin et al’s recently published Letter to the editor.In particular,we focus on the potential use of glucagon-like peptide 1 receptor agonists(GLP-1RAs)alone,but even more so in combination therapy,as one of the most promising therapies in metabolic dysfunction-associated steatotic liver disease(MASLD),the new definition of an old condition,non-alcoholic fatty liver disease,which aims to better define the spectrum of steatotic pathology.It is well known that GLP-1RAs,having shown outstanding performance in fat loss,weight loss,and improvement of insulin resistance,could play a role in protecting the liver from progressive damage.Several clinical trials have shown that,among GLP-1RAs,semaglutide is a safe,well-studied therapeutic choice for MASLD patients;however,most studies demonstrate that,while semaglutide can reduce steatosis,including steatohepatitis histological signs(in terms of inflammatory cell infiltration and hepatocyte ballooning),it does not improve fibrosis.Combinations of therapies with different but complementary mechanisms of action are considered the best way to improve efficiency and slow disease progression due to the complex pathophysiology of the disease.In particular,GLP-1RAs associated with antifibrotic drug therapy,dual glucose-dependent insulinotropic polypeptide(GIP)/GLP-1RA or GLP-1 and glucagon RAs have promoted greater improvement in hepatic steatosis,liver biochemistry,and non-invasive fibrosis tests than monotherapy.Therefore,although to date there are no definitive indications from international drug agencies,there is the hope that soon the therapeutic lines in the most advanced phase of study will be able to provide a therapy for MASLD,one that will certainly include the use of GLP-1RAs as combination therapy.

Cumulative effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease in China

BACKGROUND Within the normal range,elevated alanine aminotransferase(ALT)levels are associated with an increased risk of metabolic dysfunction-associated fatty liver disease(MAFLD).AIM To investigate the associations between repeated high-normal ALT measurements and the risk of new-onset MAFLD prospectively.METHODS A cohort of 3553 participants followed for four consecutive health examinations over 4 years was selected.The incidence rate,cumulative times,and equally and unequally weighted cumulative effects of excess high-normal ALT levels(ehALT)were measured.Cox proportional hazards regression was used to analyse the association between the cumulative effects of ehALT and the risk of new-onset MAFLD.RESULTS A total of 83.13%of participants with MAFLD had normal ALT levels.The incidence rate of MAFLD showed a linear increasing trend in the cumulative ehALT group.Compared with those in the low-normal ALT group,the multivariate adjusted hazard ratios of the equally and unequally weighted cumulative effects of ehALT were 1.651[95%confidence interval(CI):1.199-2.273]and 1.535(95%CI:1.119-2.106)in the third quartile and 1.616(95%CI:1.162-2.246)and 1.580(95%CI:1.155-2.162)in the fourth quartile,respectively.CONCLUSION Most participants with MAFLD had normal ALT levels.Long-term high-normal ALT levels were associated with a cumulative increased risk of new-onset MAFLD.

Metabolic dysfunction-associated steatotic liver disease:Navigating terminological evolution,diagnostic frontiers and therapeutic horizon-an editorial exploration

Metabolic dysfunction-associated steatotic liver disease(MASLD),once known as non-alcoholic fatty liver disease(NAFLD),represents a spectrum of liver disorders characterized by lipid accumulation within hepatocytes.The redefinition of NAFLD in 2023 marked a significant reposition in terminology,emphasizing a broader understanding of liver steatosis and its associated risks.MASLD is now recognized as a major risk factor for liver cirrhosis,hepatocellular carcinoma,and systemic complications such as cardiovascular diseases or systemic inflammation.Diagnostic challenges arise,particularly in identifying MASLD in lean individuals,necessitating updated diagnostic protocols and investing in non-invasive diagnostic tools.Therapeutically,there is an urgent need for effective treatments targeting MASLD,with emerging pharmacological options focusing on,among others,carbohydrate and lipid metabolism.Additionally,understanding the roles of bile acid metabolism,the microbiome,and dietary interventions in MASLD pathogenesis and management holds promise for innovative therapeutic approaches.There is a strong need to emphasize the importance of collaborative efforts in understanding,diagnosing,and managing MASLD to improve physicians’approaches and patient outcomes.

Metabolic disease and the liver: A review

Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most common liver disease worldwide,with an estimated prevalence of 31%in Latin America.The presence of metabolic comorbidities coexisting with liver disease varies substantially among populations.It is acknowledged that obesity is boosting the type 2 diabetes mellitus“epidemic,”and both conditions are significant contributors to the increasing number of patients with MASLD.Nonalcoholic steatohepatitis represents a condition of chronic liver inflammation and is considered the most severe form of MASLD.MASLD diagnosis is based on the presence of steatosis,noninvasive scores and altered liver tests.Noninvasive scores of liver fibrosis,such as serum biomarkers,which should be used in primary care to rule out advanced fibrosis,are simple,inexpensive,and widely available.Currently,guidelines from international hepatology societies recommend using noninvasive strategies to simplify case finding and management of high-risk patients with MASLD in clinical practice.Unfortunately,there is no definite pharmacological treatment for the condition.Creating public health policies to treat patients with risk factors for MASLD prevention is essential.

Back to the drawing board:Overview of the next generation of combination therapy for inflammatory bowel disease

Inflammatory bowel disease(IBD)is entering a potentially new era of combined therapeutics.Triantafillidis et al provide an insightful review of the current state of combination therapy,with a focus on the use of a combined biologic and immunomodulator,as well as emerging data on the future potential of dual-biologic therapy(DBT).While current evidence for DBT is limited,encouraging safety profiles and ongoing trials suggest a brighter future for this approach.The importance of controlled trials should be stressed in establishing new treatment paradigms.Ongoing prospective randomized trials of DBT and perhaps future combinations of biologics and small molecule therapies will hopefully guide the next generation of IBD care.

Role of gut-liver axis and glucagon-like peptide-1 receptor agonists in the treatment of metabolic dysfunction-associated fatty liver disease

Metabolic dysfunction-associated fatty liver disease(MAFLD)is a hepatic manifestation of the metabolic syndrome.It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries.MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma.Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis.The mechanisms involved in maintaining gut-liver axis homeostasis are complex.One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gutliver axis functionality.An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis.Moreover,alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis.Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)are a class of drugs developed for the treatment of type 2 diabetes mellitus.They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis.The mechanisms reported to be involved in this effect include an improved regulation of glycemia,reduced lipid synthesis,β-oxidation of free fatty acids,and induction of autophagy in hepatic cells.Recently,multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment.A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD.This review presents the current understanding of the role of the gutliver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.