Impact of metabolic phenotype and alcohol consumption on mortality risk in metabolic dysfunction-associated fatty liver disease: a population-based cohort study.

Patients with metabolic dysfunction-associated fatty liver disease (MAFLD) often present with concomitant metabolic dysregulation and alcohol consumption, potentially leading to distinct clinical outcomes. We analyzed data from 8043 participants with MAFLD in the Thai National Health Examination Survey with linked mortality records. According to the MAFLD criteria, 1432 individuals (17.2%) were categorized as having the diabetes phenotype, 5894 (71.0%) as the overweight/obesity phenotype, and 978 (11.8%) as the lean metabolic phenotype. Over 71,145 person-years, 916 participants died. Using Cox proportional hazard models adjusting for physiological, lifestyle, and comorbid factors, both diabetes (adjusted hazards ratio [aHR] 1.59, 95% CI 1.18-2.13) and lean metabolic phenotypes (aHR 1.28, 95% CI 1.01-1.64) exhibited significantly higher mortality risk compared to the overweight/obesity phenotype. A J-shaped relationship was observed between daily alcohol consumption and the risk of all-cause mortality. Daily alcohol intake exceeding 50 g for women and 60 g for men increased the all-cause mortality risk among MAFLD individuals with the lean metabolic phenotype (aHR 3.39, 95% CI 1.02-11.29). Our study found that metabolic phenotype and alcohol consumption have interactive effects on the risk of all-cause mortality in patients with MAFLD, indicating that evaluating both factors is crucial for determining prognostic outcomes and management strategies.

Prevalence of Musculoskeletal and Metabolic Disorders in Kidney Transplant Recipients: A Systematic Review and Meta-Analysis.

Introduction: Musculoskeletal disorders could be associated with metabolic disorders that are common after kidney transplantation, which could reduce the quality of life of patients. The aim of this study was to assess the prevalence of both musculoskeletal and metabolic disorders in kidney transplant patients. Methods: MEDLINE, CINAHL, Cochrane Library, EMBASE and Web of Science were searched from their inception up to June 2023. DerSimonian and Laird random-effects method was used to calculate pooled prevalence estimates and their 95% confidence intervals (CIs). Results: 21,879 kidney transplant recipients from 38 studies were analysed. The overall proportion of kidney transplant patients with musculoskeletal disorders was 27.2% (95% CI: 18.4-36.0), with low muscle strength (64.5%; 95% CI: 43.1-81.3) being the most common disorder. Otherwise, the overall proportion of kidney transplant patients with metabolic disorders was 37.6% (95% CI: 21.9-53.2), with hypovitaminosis D (81.8%; 95% CI: 67.2-90.8) being the most prevalent disorder. Conclusion: The most common musculoskeletal disorders were low muscle strength, femoral osteopenia, and low muscle mass. Hypovitaminosis D, hyperparathyroidism, and hyperuricemia were also the most common metabolic disorders. These disorders could be associated with poorer quality of life in kidney transplant recipients. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier [CRD42023449171].

The potential association between metabolic disorders and pulmonary tuberculosis: a Mendelian randomization study.

BACKGROUND: Metabolic disorders (MetDs) have been demonstrated to be closely linked to numerous diseases. However, the precise association between MetDs and pulmonary tuberculosis (PTB) remains poorly understood. METHOD: Summary statistics for exposure and outcomes from genome-wide association studies (GWASs) for exposures and outcomes were obtained from the BioBank Japan Project (BBJ) Gene-exposure dataset. The 14 clinical factors were categorized into three groups: metabolic laboratory markers, blood pressure, and the MetS diagnostic factors. The causal relationship between metabolic factors and PTB were analyzed using two-sample Mendelian Randomization (MR). Additionally, the direct effects on the risk of PTB were investigated through multivariable MR. The primary method employed was the inverse variance-weighted (IVW) model. The sensitivity of this MR analysis was evaluated using MR-Egger regression and the MR-PRESSO global test. RESULTS: According to the two-sample MR, HDL-C, HbA1c, TP, and DM were positively correlated with the incidence of active TB. According to the multivariable MR, HDL-C (IVW: OR 2.798, 95% CI 1.484-5.274, P = 0.001), LDL (IVW: OR 4.027, 95% CI 1.140-14.219, P = 0.03) and TG (IVW: OR 2.548, 95% CI 1.269-5.115, P = 0.009) were positively correlated with the occurrence of PTB. TC (OR 0.131, 95% CI 0.028-0.607, P = 0.009) was negatively correlated with the occurrence of PTB. We selected BMI, DM, HDL-C, SBP, and TG as the diagnostic factors for metabolic syndrome. DM (IVW, OR 1.219, 95% CI 1.040-1.429 P = 0.014) and HDL-C (IVW, OR 1.380, 95% CI 1.035-1.841, P = 0.028) were directly correlated with the occurrence of PTB. CONCLUSIONS: This MR study demonstrated that metabolic disorders, mainly hyperglycemia, and dyslipidemia, are associated with the incidence of active pulmonary tuberculosis.

Understanding the interactions between repurposed drugs sertindole and temoporfin with receptor for advanced glycation endproducts: Therapeutic implications in cancer and metabolic diseases.

CONTEXT: In the pursuit of novel therapeutic possibilities, repurposing existing drugs has gained prominence as an efficient strategy. The findings from our study highlight the potential of repurposed drugs as promising candidates against receptor for advanced glycation endproducts (RAGE) that offer therapeutic implications in cancer, neurodegenerative conditions and metabolic syndromes. Through careful analyses of binding affinities and interaction patterns, we identified a few promising candidates, ultimately focusing on sertindole and temoporfin. These candidates exhibited exceptional binding affinities, efficacy, and specificity within the RAGE binding pocket. Notably, they displayed a pronounced propensity to interact with the active site of RAGE. Our investigation further revealed that sertindole and temoporfin possess desirable pharmacological properties that highlighted them as attractive candidates for targeted drug development. Overall, our integrated computational approach provides a comprehensive understanding of the interactions between repurposed drugs, sertindole and temoporfin and RAGE that pave the way for future experimental validation and drug development endeavors. METHODS: We present an integrated approach utilizing molecular docking and extensive molecular dynamics (MD) simulations to evaluate the potential of FDA-approved drugs, sourced from DrugBank, against RAGE. To gain deeper insights into the binding mechanisms of the elucidated candidate repurposed drugs, sertindole and temoporfin with RAGE, we conducted extensive all-atom MD simulations, spanning 500 nanoseconds (ns). These simulations elucidated the conformational dynamics and stability of the RAGE-sertindole and RAGE-temoporfin complexes.

[Clinical status and challenges of new drugs for metabolic dysfunction-associated fatty liver disease].

Metabolic dysfunction-associated fatty liver disease (MASLD) is a major public health problem that seriously affects human health. At present, some good progress has been made in the research and development of new drugs for MASLD, but there is still great space for exploration. This paper summarizes and analyzes the reasons in the current clinical status and challenges for the research and development of new drugs for MASLD.

[Analysis of non-alcoholic fatty liver disease differences from metabolic dysfunction-associated fatty liver disease based on clinical features].

Objective: To explore the clinical features of fatty liver disease (FLD) from non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MASLD), so as to elucidate its clinical application value under three renames. Methods: Patients who were hospitalized in the Department of Hepatology, Hospital of Traditional Chinese Medicine Affiliated to Xinjiang Medical University, from January 2020 to September 2023 and met the diagnosis of NAFLD, metabolic-associated fatty liver disease (MAFLD), or MASLD were selected as the research subjects. The clinical indicators differences among the three groups of patients were compared, mainly including general information (age, gender, body mass index, past history, etc.), serological indicators (liver and kidney function, blood lipids, blood sugar, coagulation function, etc.), non-invasive liver fibrosis indicators, fat attenuation parameters, etc. Measurement data were analyzed using ANOVA and the rank sum test, while count data were analyzed using the χ(2) test. Results: NAFLD, MAFLD, and MASLD prevalence rates among 536 cases were 64.0%, 93.7%, and 100%, respectively. 318 cases (59.3%) met the three fatty liver names at the same time among them. Male population proportions in NAFLD, MAFLD, and MASLD were 30.9%, 55.8%, and 53.9%, respectively. The alcohol consumption history proportion was 0, 36.7%, and 36.0%, respectively. The smoking history proportion was 7.0%, 31.9%, and 30.6%, respectively. The body mass index was (27.66 ± 3.97), (28.33 ± 3.63), and (27.90 ± 3.89) kg/m(2), respectively. The γ-glutamyltransferase levels were 26.6 (18.0, 47.0) U/L, 31.0 (20.0, 53.0) U/L, and 30.8 (19.8, 30.8) U/L, respectively. The high-density lipoprotein cholesterol levels were 1.07 (0.90, 1.23) mmol/L, 1.02 (0.86, 1.19) mmol/L, and 1.03 (0.87,1.21) mmol/L, respectively. Sequentially measured uric acid was (322.98 ± 84.51) µmol/L, (346.57 ± 89.49) µmol/L, and (344.89 ±89.67) µmol/L, respectively. Sequentially measured creatinine was 69.6 (62.9, 79.0) µmol/L, 73.0 (65.0, 83.5) µmol/L, and 73.0 (65.0, 83.0) µmol/L, respectively. The sequential analysis of obesity proportion was 74.3%, 81.7%, and 76.5%, respectively, with statistically significant differences (P<0.05). Conclusion: Compared with the NAFLD population, the MAFLD and MASLD populations were predominantly male, obese, and had a history of smoking and drinking. The levels of γ-glutamyltransferase, uric acid, and creatinine were slightly higher, while the levels of high-density lipoprotein cholesterol were lower. MASLD appeared in NAFLD and MAFLD on the basis of inheritance and progression, emphasizing once again the important role of metabolic factors in a fatty liver.

Extent to which weight loss contributes to improving metabolic dysfunction-associated and metabolic and alcohol related/associated steatotic liver disease: a study on Japanese participants undergoing health checkups.

Introduction: The incidence of steatotic liver disease has increased in recent years. Thus, steatotic liver disease is a major public health issue in Japan. This study investigated the association between weight reduction and the remission of metabolic dysfunction-associated steatotic liver disease (MASLD)/Metabolic and alcohol related/associated liver disease (MetALD) in Japanese individuals undergoing health checkups. Methods: This retrospective observational study included 8,707 Japanese patients with MASLD/MetALD who underwent health checkups from May 2015 to March 2023. The participants were monitored for its remission at their subsequent visit. MASLD was diagnosed on abdominal ultrasonography and based on the presence of at least one of five metabolic abnormalities. The impact of body mass index (BMI) reduction on MASLD/MetALD remission was assessed via logistic regression analysis and using receiver operating characteristic curves. Results: Logistic regression analysis revealed that weight loss was significantly associated with MASLD/MetALD remission. Other factors including exercise habits and reduced alcohol consumption were significant predictors of MASLD/MetALD remission in the overall cohort and in male patients. The optimal BMI reduction cutoff values for MASLD/MetALD remission were 0.9 kg/m2 and 4.0% decrease in the overall cohort, 0.85 kg/m2 and 3.9% decrease in males, and 1.2 kg/m2 and 4.5% decrease in females. In participants with a BMI of 23 kg/m2, the cutoff values were 0.75 kg/m2 and 2.7% BMI reduction. Discussion: Weight reduction plays an important role in both MASLD and MetALD remission among Japanese individuals. That is, targeting specific BMI reduction is effective. This underscores the importance of targeted weight management strategies in preventing and managing MASLD/MetALD in the Japanese population.

Chronic lead poisoning-induced budgerigar liver damage, gut microbiota dysbiosis, and metabolic disorder.

Birds are sensitive to heavy metal pollution, and lead (Pb) contamination can negatively affect their liver and gut. Therefore, we used budgerigars to examine liver and gut toxicosis caused by Pb exposure in bird, and the possible toxic mechanisms. The findings showed Pb exposure increased liver weight and decreased body weight. Moreover, histopathological and immunofluorescence assay results demonstrated obvious liver damage and cell apoptosis increased in Pb- treated budgerigars. Quantitative polymerase chain reaction (qPCR) results also showed Pb caused an increase in apoptosis by inhibiting the PPAR-γ/PI3K/Akt pathway. The gut microbe analyses indicated Firmicutes, Proteobacteria, and Bacteroidetes were dominant microbial phyla, and Network analysis results shown Arthrobacter, Bradyrhizobium and Alloprevotella as the hubs of Modules I, II, and III, respectively. Phenylpropanoids and polyketides, Organoheterocyclic compounds, Organic oxygen compounds, and Organic nitrogen compounds were dominant metabolite superclasses. Tauroursodeoxycholic acid, taurochenodeoxycholic acid (sodium salt), and 2-[2-(5-bromo-2-pyridyl)diaz-1-enyl]-5-(diethylamino)phenol were significantly enriched in the Pb-treated group. It showed that 41 Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologues and 183 pathways differed between the Pb-treated and control budgerigars using microbial and metabolomic data. Moreover, orthogonal partial least-squares discrimination analysis (OPLS-DA) based on microbial and metabolite indicated distinct clusters in the Pb-treated and control groups. Additionally, the correlation analysis results indicated that a positive correlation for the Pb-treated and control groups between gut microbiota and metabolomic data, respectively. Furthermore, the microenvironment of the gut and liver were found to affect each other, and this study demonstrated heavy metal especially Pb may pose serious health risks to birds through the "gut-liver axis" too.

Nanozyme as a rising star for metabolic disease management.

Nanozyme, characterized by outstanding and inherent enzyme-mimicking properties, have emerged as highly promising alternatives to natural enzymes owning to their exceptional attributes such as regulation of oxidative stress, convenient storage, adjustable catalytic activities, remarkable stability, and effortless scalability for large-scale production. Given the potent regulatory function of nanozymes on oxidative stress and coupled with the fact that reactive oxygen species (ROS) play a vital role in the occurrence and exacerbation of metabolic diseases, nanozyme offer a unique perspective for therapy through multifunctional activities, achieving essential results in the treatment of metabolic diseases by directly scavenging excess ROS or regulating pathologically related molecules. The rational design strategies, nanozyme-enabled therapeutic mechanisms at the cellular level, and the therapies of nanozyme for several typical metabolic diseases and underlying mechanisms are discussed, mainly including obesity, diabetes, cardiovascular disease, diabetic wound healing, and others. Finally, the pharmacokinetics, safety analysis, challenges, and outlooks for the application of nanozyme are also presented. This review will provide some instructive perspectives on nanozyme and promote the development of enzyme-mimicking strategies in metabolic disease therapy.

Usefulness of Opuntia spp. on the Management of Obesity and Its Metabolic Co-Morbidities.

The plants of the Opuntia genus mainly grow in arid and semi-arid climates. Although the highest variety of wild species is found in Mexico, Opuntia spp. is widely distributed throughout the world. Extracts of these cacti have been described as important sources of bioactive substances that can have beneficial properties for the prevention and treatment of certain metabolic disorders. The objective of this review is to summarise the presently available knowledge regarding Opuntia ficus-indica (nopal or prickly pear), and some other species (O. streptacantha and O. robusta) on obesity and several metabolic complications. Current data show that Opuntia ficus-indica products used in preclinical studies have a significant capacity to prevent, at least partially, obesity and certain derived co-morbidities. On this subject, the potential beneficial effects of Opuntia are related to a reduction in oxidative stress and inflammation markers. Nevertheless, clinical studies have evidenced that the effects are highly contingent upon the experimental design. Moreover, the bioactive compound composition of nopal extracts has not been reported. As a result, there is a lack of information to elucidate the mechanisms of action responsible for the observed effects. Accordingly, further studies are needed to demonstrate whether Opuntia products can represent an effective tool to prevent and/or manage body weight and some metabolic disorders.

Adipose Tissue Immunometabolism: Unveiling the Intersection of Metabolic and Immune Regulation.

UNASSIGNED: Excess body weight has become a global epidemic and a significant risk factor for developing chronic diseases, which are the leading causes of worldwide morbidities. Adipose tissue (AT), primarily composed of adipocytes, stores substantial amounts of energy and plays a crucial role in maintaining whole-body glucose and lipid metabolism. This helps prevent excessive body fat accumulation and lipotoxicity in peripheral tissues. In addition, AT contains endothelial cells and a substantial population of immune cells (constituting 60-70% of non-adipocyte cells), including macrophages, T and B lymphocytes, and natural killer cells. These resident immune cells engage in crosstalk with adipocytes, contributing to the maintenance of metabolic and immune homeostasis in AT. An exacerbated inflammatory response or inadequate immune resolution can lead to chronic systemic low-grade inflammation, triggering the development of metabolic alterations and the onset of chronic diseases. This review aims to elucidate the regulatory mechanisms through which immune cells influence AT function and energy homeostasis. We also focus on the interactions and functional dynamics of immune cell populations, highlighting their role in maintaining the delicate balance between metabolic health and obesity-related inflammation. Finally, understanding immunometabolism is crucial for unraveling the pathogenesis of metabolic diseases and developing targeted immunotherapeutic strategies. These strategies may offer innovative avenues in the rapidly evolving field of immunometabolism. (Rev Invest Clin. 2024;76(2):65-79).

Liver histology is associated with long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis.

BACKGROUND: Few studies have examined the risk of long-term clinical outcomes in patients with metabolic dysfunction-associated steatohepatitis in relation to liver histology. We aimed to study this using a real-world cohort. METHODS: Adults (N = 702) recorded on Vanderbilt University Medical Center's Synthetic Derivative database (1984-2021) with evidence of metabolic dysfunction-associated steatohepatitis on liver biopsy were followed from the first biopsy until the first clinical event or last database entry (median: 4.7 y). Risks of cirrhosis (N = 650), other noncirrhotic liver-related (N = 702) and cardiovascular-related outcomes (N = 660), and mortality due to liver, cardiovascular, or cancer events (N = 660) were determined as a function of baseline histology (fibrosis stage [F], lobular inflammation grade [LI], hepatocyte ballooning grade [HB], and steatosis score) adjusting for sex, age, diabetes, and weight-loss surgery. RESULTS: Cirrhosis risk was reduced for lower versus higher fibrosis stage (HR: F0-1 vs. F3: 0.22 [95% CI: 0.12-0.42]), LI1 versus LI2-3 (0.42 [0.19-0.97]), and HB1 versus HB2 (0.20 [0.08-0.50]). Lower fibrosis stage was associated with significantly lower risks of liver-related outcomes versus F4 cirrhosis (eg, F0-1: 0.12 [0.05-0.25]), whereas no differences were seen across baseline lobular inflammation, hepatocyte ballooning, and steatosis grades/scores. Lower versus higher lobular inflammation grade was associated with lower risks for liver-related outcomes in patients with weight-loss surgery. There was a trend for lower risks for cardiovascular-related and any long-term outcomes with lower versus higher fibrosis stage. CONCLUSIONS: Fibrosis stage and lobular inflammation and hepatocyte ballooning grades predict the risk of long-term outcomes, supporting the use of these histological features as potential surrogate markers of disease progression or clinical outcomes.

Dietary Strategies in Postmenopausal Women with Chronic and Metabolic Diseases.

As women age, their nutritional needs change, governed by changes in hormones, level of physical activity, and dietary intake [...].

Vitamin D and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Novel Mechanistic Insights.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition characterized by abnormal fat accumulation in the liver, often associated with metabolic disorders. Emerging evidence suggests a potential link between vitamin D deficiency and the development and progression of MASLD. The current review provides a concise overview of recent studies uncovering novel mechanistic insights into the interplay between vitamin D and MASLD. Several epidemiological studies have highlighted a significant association between low vitamin D levels and an increased risk of MASLD. Vitamin D, traditionally known for its role in bone health, has now been recognized as a key player in various physiological processes, including immune regulation and inflammation. Experimental studies using animal models have demonstrated that vitamin D deficiency exacerbates liver steatosis and inflammation, suggesting a potential protective role against MASLD. Mechanistically, vitamin D appears to modulate MASLD through multiple pathways. Firstly, the vitamin D receptor (VDR) is abundantly expressed in liver cells, indicating a direct regulatory role in hepatic function. Activation of the VDR has been shown to suppress hepatic lipid accumulation and inflammation, providing a mechanistic basis for the observed protective effects. Additionally, vitamin D influences insulin sensitivity, a critical factor in MASLD pathogenesis. Improved insulin sensitivity may mitigate the excessive accumulation of fat in the liver, thus attenuating MASLD progression. In parallel, vitamin D exhibits anti-inflammatory properties by inhibiting pro-inflammatory cytokines implicated in MASLD pathophysiology. Experimental evidence suggests that the immunomodulatory effects of vitamin D extend to the liver, reducing inflammation and oxidative stress, key drivers of MASLD, and the likelihood of hepatocyte injury and fibrosis. Understanding the complex interplay between vitamin D and MASLD provides a basis for exploring targeted therapeutic strategies and preventive interventions. As vitamin D deficiency is a modifiable risk factor, addressing this nutritional concern may prove beneficial in mitigating the burden of MASLD and associated metabolic disorders.

Circadian dysfunction and cardio-metabolic disorders in humans.

The topic of human circadian rhythms is not only attracting the attention of clinical researchers from various fields but also sparking a growing public interest. The circadian system comprises the central clock, located in the suprachiasmatic nucleus of the hypothalamus, and the peripheral clocks in various tissues that are interconnected; together they coordinate many daily activities, including sleep and wakefulness, physical activity, food intake, glucose sensitivity and cardiovascular functions. Disruption of circadian regulation seems to be associated with metabolic disorders (particularly impaired glucose tolerance) and cardiovascular disease. Previous clinical trials revealed that disturbance of the circadian system, specifically due to shift work, is associated with an increased risk of type 2 diabetes mellitus. This review is intended to provide clinicians who wish to implement knowledge of circadian disruption in diagnosis and strategies to avoid cardio-metabolic disease with a general overview of this topic.

Gut-bacteria derived membrane vesicles and host metabolic health: a narrative review.

The intestinal microbiota, consisting of an estimated 10^10-10^11 organisms, regulate physiological processes involved in digestion, metabolism, and immunity. Surprisingly, these intestinal microorganisms have been found to influence tissues that are not directly in contact with the gut, such as adipose tissue, the liver, skeletal muscle, and the brain. This interaction takes place even when intestinal barrier function is uncompromised. An increasing body of evidence suggests that bacterial membrane vesicles (bMVs), in addition to bacterial metabolites such as short-chain fatty acids, are able to mediate effects of the microbiota on these host tissues. The ability of bMVs to dissipate from the intestinal lumen into systemic circulation hereby facilitates the transport and presentation of bacterial components and metabolites to host organs. Importantly, there are indications that the interaction between bMVs and tissues or immune cells may play a role in the etiology of (chronic metabolic) disease. For example, the gut-derived bMV-mediated induction of insulin resistance in skeletal muscle cells and pro-inflammatory signaling by adipocytes possibly underlies diseases such as type 2 diabetes and obesity. Here, we review the current knowledge on bMVs in the microbiota's effects on host energy/substrate metabolism with a focus on etiological roles in the onset and progression of metabolic disease. We furthermore illustrate that vesicle production by bacterial microbiota could potentially be modulated through lifestyle intervention to improve host metabolism.

Inhibition of activin receptor 2 signalling ameliorates metabolic dysfunction-associated steatotic liver disease in western diet/L-NAME induced cardiometabolic disease.

OBJECTIVE: Blockade of activin 2 receptor (ACVR2) signaling has been shown to improve insulin sensitivity and aid in weight loss. Inhibition of ACVR2 signaling restores cardiac function in multiple heart failure models. However, its potential in the treatment of obesity-related cardiometabolic disease remains unknown. Here, we investigated targeting ACVR2 signaling in cardiometabolic disease manifested with metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: Mice were fed a high-fat, high-sugar diet combined with the administration of nitric oxide synthase inhibitor L-NAME in drinking water, which causes hypertensive stress. For the last eight weeks, the mice were treated with the soluble ACVR2B decoy receptor (sACVR2B-Fc). RESULTS: sACVR2B-Fc protected against the development of comorbidities associated with cardiometabolic disease. This was most pronounced in the liver where ACVR2 blockade attenuated the development of MASLD including cessation of pro-fibrotic activation. It also significantly reduced total plasma cholesterol levels, impeded brown adipose tissue whitening, and improved cardiac diastolic function. In vitro, ACVR2 ligands activin A, activin B and GDF11 induced profibrotic signaling and the proliferation of human cardiac fibroblasts. CONCLUSIONS: Blockade of ACVR2B exerts broad beneficial effects for therapy of cardiometabolic disease. By reducing obesity, ameliorating cardiovascular deterioration and restraining MASLD, blockade of ACVR2B signaling proves a potential target in MASLD and its comorbidities.

Kaempferol efficacy in metabolic diseases: Molecular mechanisms of action in diabetes mellitus, obesity, non-alcoholic fatty liver disease, steatohepatitis, and atherosclerosis.

The incidence of metabolic diseases has progressively increased, which has a negative impact on human health and life safety globally. Due to the good efficacy and limited side effects, there is growing interest in developing effective drugs to treat metabolic diseases from natural compounds. Kaempferol (KMP), an important flavonoid, exists in many vegetables, fruits, and traditional medicinal plants. Recently, KMP has received widespread attention worldwide due to its good potential in the treatment of metabolic diseases. To promote the basic research and clinical application of KMP, this review provides a timely and comprehensive summary of the pharmacological advances of KMP in the treatment of four metabolic diseases and its potential molecular mechanisms of action, including diabetes mellitus, obesity, non-alcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), and atherosclerosis. According to the research, KMP shows remarkable therapeutic effects on metabolic diseases by regulating multiple signaling transduction pathways such as NF-κB, Nrf2, AMPK, PI3K/AKT, TLR4, and ER stress. In addition, the most recent literature on KMP's natural source, pharmacokinetics studies, as well as toxicity and safety are also discussed in this review, thus providing a foundation and evidence for further studies to develop novel and effective drugs from natural compounds. Collectively, our manuscript strongly suggested that KMP could be a promising candidate for the treatment of metabolic diseases.