Metabolic reprogramming: a new option for the treatment of spinal cord injury

Spinal cord injuries impose a notably economic burden on society,mainly because of the severe after-effects they cause.Despite the ongoing development of various therapies for spinal cord injuries,their effectiveness remains unsatisfactory.However,a deeper understanding of metabolism has opened up a new therapeutic opportunity in the form of metabolic reprogramming.In this review,we explore the metabolic changes that occur during spinal cord injuries,their consequences,and the therapeutic tools available for metabolic reprogramming.Normal spinal cord metabolism is characterized by independent cellular metabolism and intercellular metabolic coupling.However,spinal cord injury results in metabolic disorders that include disturbances in glucose metabolism,lipid metabolism,and mitochondrial dysfunction.These metabolic disturbances lead to corresponding pathological changes,including the failure of axonal regeneration,the accumulation of scarring,and the activation of microglia.To rescue spinal cord injury at the metabolic level,potential metabolic reprogramming approaches have emerged,including replenishing metabolic substrates,reconstituting metabolic couplings,and targeting mitochondrial therapies to alter cell fate.The available evidence suggests that metabolic reprogramming holds great promise as a next-generation approach for the treatment of spinal cord injury.To further advance the metabolic treatment of the spinal cord injury,future efforts should focus on a deeper understanding of neurometabolism,the development of more advanced metabolomics technologies,and the design of highly effective metabolic interventions.

Fanlian Huazhuo formula:A promising therapeutic approach for metabolic associated steatotic liver disease

This article reviews the study,“Fanlian huazhuo formula alleviates high-fat-dietinduced nonalcoholic fatty liver disease by modulating autophagy and lipid synthesis signaling pathway”published in the World Journal of Gastroenterology.The study explores the therapeutic potential of Fanlian Huazhuo formula(FLHZF)in treating metabolic-associated steatotic liver disease(MASLD),demonstrating that FLHZF reduces lipid accumulation,oxidative stress,and liver injury in MASLD models by modulating key signaling pathways involved in lipid metabolism and autophagy.This editorial emphasizes the potential of FLHZF as a treatment for MASLD and calls for further research to verify its clinical efficacy.

Clinical study on the effect of jejunoileal side-to-side anastomosis on metabolic parameters in patients with type 2 diabetes

BACKGROUND At present,the existing internal medicine drug treatment can alleviate the high glucose toxicity of patients to a certain extent,to explore the efficacy of laparoscopic jejunoileal side to side anastomosis in the treatment of type 2 diabetes,the report is as follows.AIM To investigate the effect of jejunoileal side-to-side anastomosis on metabolic parameters in patients with type 2 diabetes mellitus(T2DM).METHODS We retrospectively analyzed the clinical data of 78 patients with T2DM who were treated via jejunoileal lateral anastomosis.Metabolic indicators were collected preoperatively,as well as at 3 and 6 months postoperative.The metabolic indicators analyzed included body mass index(BMI),systolic blood pressure(SBP),diastolic blood pressure(DBP),fasting blood glucose(FBG),2-hour blood glucose(PBG),glycated hemoglobin(HbA1c),fasting C-peptide,2-hour C-peptide(PCP),fasting insulin(Fins),2-hour insulin(Pins),insulin resistance index(HOMA-IR),βCellular function index(HOMA-β),alanine aminotransferase,aspartate aminotransferase,serum total cholesterol(TC),low-density lipoprotein cholesterol(L DL-C),triglycerides(TG),high-density lipoprotein,and uric acid(UA)levels.RESULTS SBP,DBP,PBG,HbA1c,LDL-C,and TG were all significantly lower 3 months postoperative vs preoperative values;body weight,BMI,SBP,DBP,FBG,PBG,HbA1c,TC,TG,UA,and HOMA-IR values were all significantly lower 6 months postoperative vs at 3 months;and PCP,Fins,Pins,and HOMA-βwere all significantly higher 6 months postoperative vs at 3 months(all P<0.05).CONCLUSION Side-to-side anastomosis of the jejunum and ileum can effectively treat T2DM and improve the metabolic index levels associated with it.

Effect of bariatric surgery on metabolism in diabetes and obesity comorbidity:Insight from recent research

Obesity is a prevalent cause of diabetes mellitus(DM)and is a serious danger to human health.Type 2 DM(T2DM)mostly occurs along with obesity.Foodborne obesity-induced DM is caused by an excessive long-term diet and surplus energy.Bariatric surgery can improve the symptoms of T2DM in some obese patients.But different types of bariatric surgery may have different effects.There are some models built by researchers to discuss the surgical procedures’effects on me-tabolism in diabetes animal models and diabetes patients.It is high time to conclude all this effects and recommend procedures that can better improve metabolism.

Decoding the nexus:branched-chain amino acids and their connection with sleep,circadian rhythms,and cardiometabolic health

The sleep-wake cycle stands as an integrative process essential for sustaining optimal brain function and,either directly or indirectly,overall body health,encompassing metabolic and cardiovascular well-being.Given the heightened metabolic activity of the brain,there exists a considerable demand for nutrients in comparison to other organs.Among these,the branched-chain amino acids,comprising leucine,isoleucine,and valine,display distinctive significance,from their contribution to protein structure to their involvement in overall metabolism,especially in cerebral processes.Among the first amino acids that are released into circulation post-food intake,branched-chain amino acids assume a pivotal role in the regulation of protein synthesis,modulating insulin secretion and the amino acid sensing pathway of target of rapamycin.Branched-chain amino acids are key players in influencing the brain's uptake of monoamine precursors,competing for a shared transporter.Beyond their involvement in protein synthesis,these amino acids contribute to the metabolic cycles ofγ-aminobutyric acid and glutamate,as well as energy metabolism.Notably,they impact GABAergic neurons and the excitation/inhibition balance.The rhythmicity of branchedchain amino acids in plasma concentrations,observed over a 24-hour cycle and conserved in rodent models,is under circadian clock control.The mechanisms underlying those rhythms and the physiological consequences of their disruption are not fully understood.Disturbed sleep,obesity,diabetes,and cardiovascular diseases can elevate branched-chain amino acid concentrations or modify their oscillatory dynamics.The mechanisms driving these effects are currently the focal point of ongoing research efforts,since normalizing branched-chain amino acid levels has the ability to alleviate the severity of these pathologies.In this context,the Drosophila model,though underutilized,holds promise in shedding new light on these mechanisms.Initial findings indicate its potential to introduce novel concepts,particularly in elucidating the intricate connections between the circadian clock,sleep/wake,and metabolism.Consequently,the use and transport of branched-chain amino acids emerge as critical components and orchestrators in the web of interactions across multiple organs throughout the sleep/wake cycle.They could represent one of the so far elusive mechanisms connecting sleep patterns to metabolic and cardiovascular health,paving the way for potential therapeutic interventions.

Lipid droplets in the nervous system:involvement in cell metabolic homeostasis

Lipid droplets serve as primary storage organelles for neutral lipids in neurons,glial cells,and other cells in the nervous system.Lipid droplet formation begins with the synthesis of neutral lipids in the endoplasmic reticulum.Previously,lipid droplets were recognized for their role in maintaining lipid metabolism and energy homeostasis;however,recent research has shown that lipid droplets are highly adaptive organelles with diverse functions in the nervous system.In addition to their role in regulating cell metabolism,lipid droplets play a protective role in various cellular stress responses.Furthermore,lipid droplets exhibit specific functions in neurons and glial cells.Dysregulation of lipid droplet formation leads to cellular dysfunction,metabolic abnormalities,and nervous system diseases.This review aims to provide an overview of the role of lipid droplets in the nervous system,covering topics such as biogenesis,cellular specificity,and functions.Additionally,it will explore the association between lipid droplets and neurodegenerative disorders.Understanding the involvement of lipid droplets in cell metabolic homeostasis related to the nervous system is crucial to determine the underlying causes and in exploring potential therapeutic approaches for these diseases.

Perfluoropentane-based oxygen-loaded nanodroplets reduce microglial activation through metabolic reprogramming

Microglia,the primary immune cells within the brain,have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system,including Parkinson’s disease.Nanoscale perfluorocarbon droplets have been reported to not only possess a high oxygen-carrying capacity,but also exhibit remarkable anti-inflammatory properties.However,the role of perfluoropentane in microglia-mediated central inflammatory reactions remains poorly understood.In this study,we developed perfluoropentane-based oxygen-loaded nanodroplets(PFP-OLNDs)and found that pretreatment with these droplets suppressed the lipopolysaccharide-induced activation of M1-type microglia in vitro and in vivo,and suppressed microglial activation in a mouse model of Parkinson’s disease.Microglial suppression led to a reduction in the inflammatory response,oxidative stress,and cell migration capacity in vitro.Consequently,the neurotoxic effects were mitigated,which alleviated neuronal degeneration.Additionally,ultrahigh-performance liquid chromatography–tandem mass spectrometry showed that the anti-inflammatory effects of PFP-OLNDs mainly resulted from the modulation of microglial metabolic reprogramming.We further showed that PFP-OLNDs regulated microglial metabolic reprogramming through the AKT-mTOR-HIF-1αpathway.Collectively,our findings suggest that the novel PFP-OLNDs constructed in this study alleviate microglia-mediated central inflammatory reactions through metabolic reprogramming.

Recent advances in bariatric/metabolic surgery:appraisal of clinical evidence

Obesity and associated type 2 diabetes mellitus（T2DM） are becoming a serious medical issue worldwide.Bariatric surgery has been shown to be the most effective and durable therapy for the treatment of morbid obese patients.Increasing data indicates bariatric surgery as metabolic surgery is an effective and novel therapy for not well controlled obese T2 DM patients.The review of recent developments in bariatric/metabolic surgery covers 4major fields.1） Improvement of safety：recent advances in laparoscopic/metabolic surgery has made this minimal invasive surgery more than ten times safer than a decade ago.The safety profile of laparoscopic/metabolic surgery is compatible with that of laparoscopic cholecystectomy now.2） New bariatric/metabolic surgery：laparoscopic sleeve gastrectomy（LSG） is becoming the leading bariatric surgery because of its simplicity and efficacy.Other new procedures,such as gastric plication,banded plication,single anastomosis（mini） gastric bypass and Duodeno-jejunal bypass with sleeve gastrectomy have all been accepted as treatment modalities for bariatric/metabolic surgery.3）Mechanism of bariatric/metabolic surgery：Restriction is the most important mechanism for bariatric surgery.Weight regain after bariatric surgery is usually associated with loss of restriction.Recent studies demonstrated that gut hormone,microbiota and bile acid changes after bariatric surgery may play an important role in durable weight loss as well as in T2 DM remission.However,weight loss is still the cornerstone of T2 DM remission after metabolic surgery.4） Patient selection：patients who may benefit most from bariatric surgery was found to be patients with insulin resistance.For Asian T2 DM patients,the indication of metabolic surgery has been set to those with not well2controlled（Hb A1 c.7.5%） disease and with their BMI.27.5 Kg/m.A novel diabetes surgical score,ABCD score,is a simple system for predicting the success of surgical therapy for T2 DM.

From bariatric to metabolic surgery:Looking for a"diseasemodifier"surgery for type 2 diabetes

In this review the recent evolution of the comprehension of clinical and metabolic consequences of bariatric surgery is depicted. At the beginning bariatric surgery aim was a significant and durable weight loss. Later on, it became evident that bariatric surgery was associated with metabolic changes, activated by unknown pathways, partially or totally independent of weight loss. Paradigm of this "metabolic" surgery is its effects on type 2 diabetes mellitus(T2DM). In morbid obese subjects it was observed a dramatic metabolic response leading to decrease blood glucose, till diabetes remission, before the achievement of clinically significant weight loss, opening the avenue to search for putative antidiabetic "intestinal" factors. Both proximal duodenal(still unknown) and distal(GLP1) signals have been suggested as hormonal effectors of surgery on blood glucose decrease. Despite these findings T2 DM remission was never considered a primary indication for bariatric surgery but only a secondary one. Recently T2 DM remission in obese subjects with body mass index(BMI) greater than 35 has become a primary aim for surgery. This change supports the idea that "metabolic surgery" definition could more appropriate than bariatric, allowing to explore the possibility that metabolic surgery could represent a "disease modifier" for T2 DM. Therefore, several patients have undergone surgery with a primary aim of a definitive cure of T2 DM and today this surgery can be proposed as an alternative therapy. How much surgery can be considered truly metabolic is still unknown. To be truly "metabolic" it should be demonstrated that surgery could cause T2 DM remission not only in subjects with BMI > 35 but also with BMI < 35 or even < 30. Available evidence on this topic is discussed in this mini-review.

Metabolic bariatric surgery and type 2 diabetes mellitus:an endocrinologist's perspective

Traditional treatment of T2 DM consisting of modification of diet,an exercise regimen,and pharmacotherapy has problems of poor lifestyle modifications and fail tend of treatment over time,now bariatric surgery is recommended for treatment of obese patients with T2 DM because its great improvements on weight loss and metabolic.In this article,effects of bariatric surgery on diabetes and diabetes-related complications are reviewed.

Bariatric surgery-mediated weight loss and its metabolic consequences for type-2 diabetes

The worldwide epidemic of obesity and its medical complications are being dealt with a combination of life style changes(e.g.,healthier diet and exercise),medications and a variety of surgical interventions.The Roux-en Y gastric bypass(RYGB) and laparoscopic adjustable gastric banding(LAGB) are two of the most common weight loss surgeries for morbid obesityassociated metabolic syndrome and insulin resistance.A vast majority of patients that undergo RYGB and LAGB are known to experience marked weight loss and attenuation of diabetes.A number of recent studies have indicated that the rates of remission in glycemic control and insulin sensitivity are significantly greater in patients that have undergone RYGB.A plausible hypothesis to explain this observation is that the gastric bypass surgery as opposed to the gastric banding procedure impinges on glucose homeostasis by a weight loss-independent mechanism.In a recent paper,Bradley et al have experimentally explored this hypothesis.The authors compared several clinical and laboratory parameters of insulin sensitivity and β-cell function in cohorts of RYGB and LAGB patients before and after they lost approximately 20% of their body mass.Afterweight loss,both groups of patients underwent similar changes in their intra-abdominal and total adipose tissue volume,hepatic triglyceride and circulating leptin levels.The RYGB patients who lost 20% body mass,manifested higher postprandial output of glucose,insulin and glucagon-like peptide-1;these laboratory parameters remained unchanged in LABG patients.Irrespective of the observed differences in transient responses of RYGB and LAGB patients to mixed meal,the overall glycemic control as judged by glucose tolerance,multi-organ insulin sensitivity and β-cell function were nearly identical in the two groups.Both RYGB and LAGB patient cohorts also experienced similar changes in the expression of a number of pro-and anti-inflammatory markers.Based on these analyses,Bradley et al concluded that similar restoration of insulin sensitivity and b-cell function in non-diabetic obese patients that have undergone RYGB and LAGB were directly due to marked weight loss.These data have important implications for the risk/benefit analysis of weight loss therapy by bariatric procedures.

Effect of bariatric surgery on humoral control of metabolic derangements in obese patients with type 2 diabetes mellitus: How it works

Obesity and diabetes is a co-pandemic and amajor health concern that is expanding. It has many psychosocial and economic consequences due to morbidity and mortality of this disease combination. The pathophysiology of obesity and related diabetes is complex and multifactorial. One arm of this disease process is the genetic susceptibility. Other arm is dependent on the intricate neuro-humoral factors that converge in the central nerve system. Gut hormones and the adipose tissue derived factors plays an important role in this delicate network. Bariatric surgery provides the only durable option for treatment of obesity and furthermore it provides a remission in the concomitant diseases that accompany obesity. This review provides a brief insight to all these mechanisms and tries to deduce the possible reasons of remission of type 2 diabetes after bariatric surgery.

Metabolic syndrome and liver disease in the era of bariatric surgery: What you need to know!

Metabolic syndrome(MS)is defined as the constellation of obesity,insulin resistance,high serum triglycerides,low high-density lipoprotein cholesterol,and high blood pressure.It increasingly affects more and more people and progressively evolves into a serious issue with widespread healthcare,cost,and quality of life associated consequences.MS is associated with increased morbidity and mortality due to cardiovascular or chronic liver disease.Conservative treatment,which includes diet,exercise,and antidiabetic agents,is the mainstay of treatment,but depends on patient compliance to medical treatment and adherence to lifestyle modification recommendations.Bariatric surgery has recently emerged as an appropriate alternative treatment with promising longterm results.Sleeve gastrectomy and Roux-en-Y gastric bypass constitute the most commonly performed procedures and have been proven both cost-effective and safe with low complication rates.Liver transplantation is the only definitive treatment for end-stage liver disease and its utilization in patients with nonalcoholic steatohepatitis has increased more than fivefold over the past 15 years.In this review,we summarize current state of evidence on the surgical treatment of MS.

Effect of bariatric surgery on adiposity and metabolic profiles: A prospective cohort study in Middle-Eastern patients

AIM To investigate changes in adiposity and cardio-metabolic risk profile following Roux-en-Y gastric bypass in patients of Middle Eastern ethnicity with severe obesity.METHODS This prospective cohort study involved 92 patients who met the indications of bariatric surgery. Post-procedure markers of obesity and cardiometabolic profile were monitored regularly for a year.RESULTS Mean body mass index decreased by 29.5% from 41.9 to 29.5 kg/m^2 between baseline and 12-mo follow-up, while mean fat mass decreased by 45.9% from 64.2 kg to 34.7 kg. An improvement was also observed in the glucometabolic profile with both fasting glucose and HbA 1csubstantially decreasing(P < 0.001).CONCLUSION The present study shows the short to medium term(1 year) health benefits of bariatric surgery for patients of Middle Eastern ethnicity.

Role of nutritional ketosis in the improvement of metabolic parameters following bariatric surgery

BACKGROUND Ketone bodies(KB)might act as potential metabolic modulators besides serving as energy substrates.Bariatric metabolic surgery(BMS)offers a unique opportunity to study nutritional ketosis,as acute postoperative caloric restriction leads to increased lipolysis and circulating free fatty acids.AIM To characterize the relationship between KB production,weight loss(WL)and metabolic changes following BMS.METHODS For this retrospective study we enrolled male and female subjects aged 18-65 years who underwent BMS at a single Institution.Data on demographics,anthropometrics,body composition,laboratory values and urinary KB were collected.RESULTS Thirty-nine patients had data available for analyses[74.4%women,mean age 46.5±9.0 years,median body mass index 41.0(38.5;45.4)kg/m^(2),fat mass 45.2%±6.2%,23.1%had diabetes,43.6%arterial hypertension and 74.4%liver steatosis].At 46.0±13.6 d post-surgery,subjects had lost 12.0%±3.6%of pre-operative weight.Sixty-nine percent developed ketonuria.Those with nutritional ketosis were significantly younger[42.9(37.6;50.7)years vs 51.9(48.3;59.9)years,P=0.018],and had significantly lower fasting glucose[89.5(82.5;96.3)mg/dL vs 96.0(91.0;105.3)mg/dL,P=0.025]and triglyceride levels[108.0(84.5;152.5)mg/dL vs 152.0(124.0;186.0)mg/dL,P=0.045]vs those with ketosis.At 6 mo,percent WL was greater in those with postoperative ketosis(-27.5%±5.1%vs 23.8%±4.3%,P=0.035).Urinary KBs correlated with percent WL at 6 and 12 mo.Other metabolic changes were similar.CONCLUSION Our data support the hypothesis that subjects with worse metabolic status have reduced ketogenic capacity and,thereby,exhibit a lower WL following BMS.

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.

Bariatric surgery and diabetes:Current challenges and perspectives

Diabetes mellitus(DM)and obesity have become public issues of global concern.Bariatric surgery for the treatment of obesity combined with type 2 DM has been shown to be a safe and effective approach;however,there are limited studies that have systematically addressed the challenges of surgical treatment of obesity combined with DM.In this review,we summarize and answer the most pressing questions in the field of surgical treatment of obesity-associated DM.I believe that our insights will be of great help to clinicians in their daily practice.

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.

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.

FibroScan-aspartate transaminase:A superior non-invasive model for diagnosing high-risk metabolic dysfunction-associated steatohepatitis

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)with hepatic histological NAFLD activity score≥4 and fibrosis stage F≥2 is regarded as“at risk”non-alcoholic steatohepatitis(NASH).Based on an international consensus,NAFLD and NASH were renamed as metabolic dysfunction-associated steatotic liver disease(MASLD)and metabolic dysfunction-associated steatohepatitis(MASH),respectively;hence,we introduced the term“high-risk MASH”.Diagnostic values of seven non-invasive models,including FibroScan-aspartate transaminase(FAST),fibrosis-4(FIB-4),aspartate transaminase to platelet ratio index(APRI),etc.for high-risk MASH have rarely been studied and compared in MASLD.AIM To assess the clinical value of seven non-invasive models as alternatives to liver biopsy for diagnosing high-risk MASH.METHODS A retrospective analysis was conducted on 309 patients diagnosed with NAFLD via liver biopsy at Beijing Ditan Hospital,between January 2012 and December 2020.After screening for MASLD and the exclusion criteria,279 patients wereincluded and categorized into high-risk and non-high-risk MASH groups.Utilizing threshold values of each model,sensitivity,specificity,positive predictive value(PPV),and negative predictive values(NPV),were calculated.Receiver operating characteristic curves were constructed to evaluate their diagnostic efficacy based on the area under the curve(AUROC).RESULTS MASLD diagnostic criteria were met by 99.4%patients with NAFLD.The MASLD population was analyzed in two cohorts:Overall population(279 patients)and the subgroup(117 patients)who underwent liver transient elastography(FibroScan).In the overall population,FIB-4 showed better diagnostic efficacy and higher PPV,with sensitivity,specificity,PPV,NPV,and AUROC of 26.9%,95.2%,73.5%,72.2%,and 0.75.APRI,Forns index,and aspartate transaminase to alanine transaminase ratio(ARR)showed moderate diagnostic efficacy,whereas S index and gamma-glutamyl transpeptidase to platelet ratio(GPR)were relatively weaker.In the subgroup,FAST had the highest diagnostic efficacy,its sensitivity,specificity,PPV,NPV,and AUROC were 44.2%,92.3%,82.1%,67.4%,and 0.82.The FIB-4 AUROC was 0.76.S index and GPR exhibited almost no diagnostic value for high-risk MASH.CONCLUSION FAST and FIB-4 could replace liver biopsy as more effectively diagnostic methods for high-risk MASH compared to APRI,Forns index,ARR,S index,and GPR;FAST is superior to FIB-4.