Quick glance at 'metabolic dysfunction associated steatotic liver disease' therapeutics: Targets, trials, and trends

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), recognized as the most prevalent liver disease worldwide and a leading cause of liver transplantation, is closely associated with type 2 diabetes, cardiovascular disease, and metabolic dysfunction. Its multifactorial pathogenesis involves insulin resistance, lipotoxicity, gut dysbiosis, and dysregulated signaling involving multiple receptors and pathways, culminating in hepatic steatosis, inflammation, fibrosis, and, ultimately, cirrhosis. Emerging insights into bile acid metabolism, short-chain fatty acids, and fibrogenic mediators underscore the complexity of disease progression. Despite increasing global prevalence, effective pharmacological treatments remain limited. Resmetirom, a thyroid hormone receptor β (THR-β) agonist, is currently the lone agent approved for treating metabolic dysfunction-associated steatohepatitis (MASH). Off-label use of vitamin E and obeticholic acid has met with some treatment success. Peroxisome proliferator-activated receptor (PPAR) agonists, novel antidiabetic agents, glucagon-like peptide 1 agonists, and sodium-glucose cotransporter 2 inhibitors have shown promising results in MASLD/MASH; however, further data are needed to prove their efficacy and safety. While metformin has largely failed to demonstrate efficacy, hepatotoxicity remains an area of concern with statin therapy. Novel agents, such as fibroblast growth factor analogs, fatty acid synthase inhibitors, galectin-3 inhibitors, and stearoyl-CoA desaturase inhibitors, are in the early stages of development and trials, warranting further research in steatotic liver diseases. Despite encouraging advances, long-term safety, durability of response, and regulatory approvals remain key hurdles before these agents can be broadly implemented in clinical practice. This review summarizes current knowledge on the pathogenesis of MASLD/MASH and the molecular pathways that may offer therapeutic potential in managing this widespread metabolic liver disease.

Key Words: Metabolic dysfunction-associated steatotic liver disease; Metabolic dysfunction-associated steatohepatitis; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Resmetirom; Fatty liver; Vitamin E; Insulin resistance; Obeticholic acid

Core Tip: Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), have emerged as leading causes of chronic liver disease globally, paralleling the rise in obesity, type 2 diabetes, and metabolic syndrome. These conditions significantly increase the risk of cirrhosis, and hepatocellular carcinoma, creating an urgent need for effective treatment strategies. Recent advances in pharmacotherapy, including agents targeting metabolic pathways, inflammation, and fibrosis offer promising and novel therapeutic landscapes. Early recognition and intervention are essential to prevent disease progression and reduce the growing global burden of MASLD/MASH.

INTRODUCTION

From a hepatology perspective, the most significant development in 2023 was likely the change in nomenclature from nonalcoholic fatty liver disease (NAFLD) to MASLD. Accordingly, nonalcoholic steatohepatitis (NASH) was replaced by MASH. The NAFLD or MASLD spectrum constitutes the most frequent liver disease worldwide. In 2016, a meta-analysis with more than eight million subjects reported a global prevalence of 25.2% of NAFLD[1]. The prevalence is much higher in individuals with type 2 diabetes mellitus (T2DM), as high as 65%[2]. MASLD is a risk factor for cirrhosis and hepatocellular cancer (HCC) and is the most common indication for liver transplantation in the United States. It is closely related to cardiovascular diseases, which are also the most common cause of mortality in MASLD[3]. First reported by Ludwig et al[4] in 1980, little progress has been made in the pharmacotherapy of NAFLD/MASLD over the past quarter-century. This review article explores the available pharmacological options and their clinical evidence in treating the most common global liver disease.

PATHOGENESIS

MASLD is a complex and multifactorial disease with a spectrum ranging from simple steatosis to concomitant inflammation, fibrosis, and cirrhosis (Figure 1). A "multiple-hit hypothesis" better explains the pathogenesis, which encompasses genetic and environmental factors, diet, insulin resistance, lipotoxicity, cytokines, gut dysbiosis, and other factors (Figure 1)[5]. The exact role of these factors and the sequence of events leading to the onset or progression of fatty liver disease remain elusive.

Figure 1 Natural history and pathogenesis of metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis. The metabolic dysfunction-associated steatotic liver disease spectrum extends from simple steatosis to steatohepatitis to fibrosis and cirrhosis and could predispose to hepatocellular carcinoma. The "multiple hit" hypothesis best explains the pathogenesis, although the sequence or influence of each hit is unclear and may vary between individual patients.

Genetic factors

Genetic factors are believed to play a key role in the pathogenesis of MASH/MASLD, which could explain the regional and ethnic variability in the incidence, progression, and severity of steatotic liver diseases. It is considered to be a polygenic disorder; a few implicated include patatin-like phospholipase domain-containing protein 3 (PNPLA3), fat mass and obesity-associated, sterol regulatory element-binding protein 1 (SREBP1), insulin receptor, torsin family 1-member B, glucuronidase beta, membrane-bound O-acyltransferase domain-containin/transmembrane channel-like 4, cordon-bleu WH2 repeat protein like 1/growth factor receptor-bound protein 14 and protein tyrosine phosphatase receptor type D genes. The PNPLA3 I148M variant and the TM6SF2 E167K variant are the best-studied genetic variants strongly associated with MASLD/MASH. Conversely, specific genetic variants of Pleckstrin and Sec7 domain-containing 3, alcohol dehydrogenase 1B, and mammalian tribbles homolog 1 confer protection against steatotic liver diseases[6]. First-degree relatives of patients with MASLD cirrhosis carry a 12-fold higher risk of advanced fibrosis[7]. A family history of hepatic steatosis does increase an individual's risk by nearly two-fold[8]. Twin studies reveal high concordance in hepatic steatosis and fibrosis between monozygotic but not dizygotic twins[9].

Insulin resistance: Insulin plays a crucial role in lipid metabolism by increasing lipogenesis and decreasing lipolysis. It inhibits hormone-sensitive lipases in adipose tissue. Quantitative insulin deficiency or insulin resistance promotes adipolysis, increasing the availability of circulating free fatty acids (FFA). The liver takes the circulating FFAs with the help of fatty acid translocase (CD36) and fatty acid-binding proteins. Within the hepatocytes, the FFA undergoes beta-oxidation or esterification to generate triglycerides. Insulin resistance and subsequent hyperinsulinemia promote hepatic FFA uptake and esterification, while inhibiting beta-oxidation, leading to the accumulation of triglycerides within hepatocytes, a condition known as fatty liver[10-12]. This 'paradoxical hepatic lipogenesis', unlike the lipolysis in the periphery, is at least partially explained by the upregulation of sterol regulatory element binding protein 1c, a transcription factor induced by hyperinsulinemia in the liver. Hyperinsulinemia also promotes the activity of hepatic acetyl-CoA carboxylase and fatty acid synthase, contributing to hepatic de novo lipogenesis, which converts glucose into fatty acids and triglycerides within the liver[13,14]. The role of insulin resistance in the pathogenesis of MASLD/MASH is depicted in Figure 2.

Figure 2 Insulin resistance and metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis. Insulin resistance promotes adipolysis, culminating in a flux of circulating free fatty acids (FFA). Within the liver, FFAs are esterified to form triglycerides, which are deposited in the hepatocyte cytosol, leading to hepatic steatosis. Alternatively, they interact with apolipoproteins to form very low-density lipoproteins. The free fatty acids also undergo fatty acid oxidation, primarily in the mitochondria. Insulin resistance is associated with mitochondrial dysfunction and reduced hepatic fatty acid oxidation. The hyperinsulinemia and hyperglycemia, in the setting of insulin resistance, further enhance hepatic de novo lipogenesis via sterol regulatory element-binding protein 1 and carbohydrate response element binding protein, respectively. FFA: Free fatty acids; T2DM: Type 2 diabetes mellitus; VLDL: Very-low-density lipoprotein.

Lipotoxicity is believed to be a primary contributor to the progression of fatty liver disease to steatohepatitis and ultimately to fibrosis and cirrhosis. Excess FFA in the liver, especially in cases of insulin resistance, overwhelms the hepatic capacity to handle it. The excess FFA is metabolized into intermediates such as ceramides, diacylglycerol, and lysophosphatidylcholine, which can be potentially hepatotoxic. The excess mitochondrial oxidation of FFA generates oxygen-free radicals, oxidative stress, and mitochondrial dysfunction. The FFA also impairs the protein folding function of the endoplasmic reticulum. In addition to promoting hepatocyte apoptosis, lipotoxicity contributes to an inflammatory response through the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and c-Jun N-terminal kinase (JNK) pathways. The loss of hepatocytes and inflammation activate hepatic stellate cells, leading to the deposition of extracellular matrix, fibrosis, and, ultimately, cirrhosis[15-18].

Gut dysbiosis: Alterations in the intestinal microbiome, characterized by increased loads of harmful bacteria and a decline in favorable fauna, are associated with diet, lifestyle, and host environmental or genetic factors. Studies in MASLD/MASH have revealed a higher Firmicutes/Bacteroidetes (F/B) ratio. At the genus level, an increase in Escherichia, Prevotella, Shigella, and Streptococcus has been reported in NAFLD[19,20]. The Enterobacteriaceae contribute to the synthesis of endogenous alcohol and endotoxin[20]. Eubacterium, Lachnospiraceae, and Subdoligranulum, the bacteria that produce short-chain fatty acids (SCFAs), are depleted in obesity and NAFLD[20]. Intestinal bile acid metabolism is closely linked to the gut microbiome and involves several processes, including deconjugation, dihydroxylation, oxidation, and sulfation, among others. Bile acids exert regulatory effects on bacterial colonies due to their physical and antimicrobial properties[21]. The microbiome-bile acid interplay is intricate, and gut dysbiosis impacts bile acid homeostasis. The altered bile acid proportions are frequently reported in NAFLD/NASH[22]. Overall, gut dysbiosis contributes to the spectrum of steatotic liver disease by altering intestinal permeability, inducing endotoxemia, disrupting the bile acid pool, and promoting endogenous alcohol synthesis[23].

SCFA: SCFA plays an integral role in maintaining the mucosal barrier by providing nutrition to colonocytes, increasing the expression of tight junctions, and synthesizing mucin. SCFA interacts with free fatty acid receptors FFAR2 and FFAR3 and increases the secretion of peptide YY (PYY) and GLP-1 by the intestinal L-cells. The PYY is an anorexigenic hormone and an inhibitor of gastric emptying, which induces satiety. GLP-1 induces insulin secretion while suppressing glucagon synthesis and gastric emptying[24]. The SCFA exhibits anti-inflammatory activity by inhibiting histone deacetylases in the T cells[25]. Butyrate is also postulated to suppress the NF-kB signaling and enhance the expression of anti-inflammatory cytokines[26]. Alterations in the gut microbiome negatively affect the synthesis of SCFA, subsequently increasing the risk of cardiometabolic and steatotic liver diseases.

Farnesoid X receptor: Farnesoid X receptor (FXR) is a nuclear hormone receptor expressed at the highest density in the intestine and liver. It is also known as a bile acid receptor, as its natural ligands are bile acids. However, besides bile acid homeostasis, they play crucial roles in glucose and lipid metabolism, liver growth and regeneration, and immune responses[27]. The enterocyte FXR, when activated by the bile acids, generates FGF19, which binds with fibroblast growth factor receptor 4 (FGFR4) in the liver and suppresses the cytochrome P450 enzymes, CYP7A1 and CYP8B1, responsible for bile acid synthesis[27]. The key regulator of hepatic lipogenesis, sterol regulatory element binding protein 1c, is downregulated by the activation of FXR. FXR activation also suppresses IR, gluconeogenesis, and inflammatory response, enhancing liver regeneration through multiple pathways. FXR-deficient animal models display hyperglycemia, hypertriglyceridemia, hepatic steatosis, inflammation, and fibrosis[28]. Yang et al[29] have demonstrated decreased FXR expression in patients with NAFLD[29].

Thyroid hormones and receptors: Thyroid hormones have pleiotropic effects, with metabolic impacts being the most well-known. Hypothyroidism is associated with elevated levels of total cholesterol, low-density lipoproteins (LDL), and triglycerides. A higher incidence of hypercholesterolemia, cardiovascular diseases, and NAFLD/NASH has been observed in subclinical and clinical hypothyroidism[30]. Interestingly, studies have reported a higher risk of NASH, over and above NAFLD, in patients with hypothyroidism[30,31]. The nuclear THR-β mediate the effects of thyroid hormones. The α isoform is primarily expressed in the cardiac and skeletal muscles, bone, and brain, while the β isoform is mainly expressed in the liver, kidney, and pituitary[32]. The net impact of hepatic THR-β activity on lipid metabolic pathways is the clearance of intrahepatic fat via enhanced intrahepatic lipolysis, lipophagy, β-oxidation, and bile acid synthesis (Figure 3)[33]. In animal models, loss-of-function THR-β mutations have been associated with hepatic steatosis[34]. Furthermore, thyroid hormones and THR-β ligands reduced hepatic triglyceride content, suggesting their potential role in the pathogenesis of steatotic liver diseases[23-36].

Figure 3 The nuclear thyroid hormone receptor β - retinoid X receptor heterodimer is physiologically activated by triiodothyronine (T3). Resmetirom, a liver-directed agonist of thyroid hormone receptor β (THRβ), interacts with the THRβ - retinoid X receptor heterodimer to activate the thyroid hormone response elements, resulting in selective messenger ribonucleoprotein (mRNA) transcription and protein translation. The resultant proteins promote mitophagy (the removal of damaged mitochondria), mitochondrial biogenesis, and mitochondrial fatty acid oxidation, allowing for improved clearance of free fatty acids. It suppresses hepatic de novo lipogenesis by downregulating sterol regulatory element-binding protein 1c, fatty acid synthase, and acetyl-CoA carboxylase 1. Additional proteins: Cytochrome P450, family 7, subfamily A, polypeptide 1 increases bile acid synthesis; hydroxymethylglutaryl-CoA reductase increases cholesterol synthesis; the low-density lipoprotein receptor increases hepatic low-density lipoproteins uptake. RXR: Retinoid X receptor; TRE: Thyroid hormone response elements; LDL: Low-density lipoproteins; LDL-R: Low-density lipoprotein receptor; THRβ: Thyroid hormone receptor β.

PPAR: PPARs are nuclear receptors that, upon activation by ligand interaction, promote the transcription of a wide range of genes involved in lipid and glucose homeostasis, energy balance, inflammation, and other processes[37]. The isoform PPARβ/δ is ubiquitously expressed, while PPARα is predominant in the liver and muscles, and PPARγ is concentrated in adipose tissue, as well as to a lesser extent in the liver. The endogenous PPAR ligands include free fatty acids, eicosanoids, and other complex lipids[38]. PPARα stimulates fatty acid β-oxidation, ketogenesis, and bile acid biosynthesis, thereby facilitating the clearance of intrahepatic fat. PPARγ improves insulin sensitivity and attenuates lipotoxicity. PPARγ and PPARβ/δ also promote tissue fatty acid oxidation, though to a lesser extent compared to PPARα[39]. The PPARγ receptors expressed on hepatic stellate cells are proposed to downregulate cellular activation, thereby maintaining a quiescent state and inhibiting fibrogenesis[40].

Fibrosis: The onset and progression of fibrosis have detrimental effects on outcomes of MASLD/MASH. Histologically graded by METAVIR score, hepatic fibrosis ranges from no fibrosis (F0) to cirrhosis (F4)[41]. Fibrosis is the final common pathway in all liver diseases, leading to cirrhosis. Advancing hepatic fibrosis predicts poorer liver outcomes, development, and mortality. Hepatic lipotoxicity and oxidative stress induce hepatocyte injury and apoptosis, releasing decay-associated molecular patterns. These, along with pathogen-associated molecular patterns resulting from endotoxemia caused by gut dysbiosis and altered intestinal permeability, initiate the inflammatory cascade. The inflammatory cytokines and several growth factors intricately modulate the proliferation, contractility, and extracellular matrix deposition of hepatic stellate cells, ultimately leading to the development of fibrosis and cirrhosis. An exhaustive list of factors, including the likes of platelet-derived growth factor, transforming growth factor beta-1, FGF, connective tissue growth factor, vascular endothelial growth factor and insulin-like growth factor, have been implicated in the process of hepatic fibrogenesis[42-44].

PHARMACOTHERAPY

Vitamin E

Vitamin E is one of the most frequently utilized medications for treating steatotic liver disease. Due to its antioxidant effects, vitamin E helps neutralize hepatic oxidative stress. Through protein kinase C inhibition, α-tocopherol inhibits cellular proliferation in various cell types, including monocytes/macrophages, neutrophils, fibroblasts, and vascular smooth muscle cells. Inhibition of the lipoxygenase pathway leads to reduced levels of IL-1β, a pro-inflammatory cytokine[45]. Vitamin E supplements increase adiponectin levels, which are capable of suppressing hepatic lipogenesis and inflammation[46]. Animal studies have demonstrated an increase in PPAR-α with α-tocopherol supplementation; higher levels improve hepatic fatty acid β-oxidation and insulin resistance[47]. The attenuation of NFK-β and JNK signaling subdues the inflammatory response in MASLD/MASH. Vitamin E upregulates the anti-apoptotic Bcl-2 while downregulating pro-apoptotic BAX and p53 proteins, resulting in a net anti-apoptotic effect. Also, it inhibits the mitochondrial caspase activity and the FAS/FAS ligand apoptotic pathway[48].

Multiple studies have demonstrated the biochemical and histological benefits of Vitamin E in fatty liver[49,50]. The PIVENS trial demonstrated a statistically significant improvement in NASH in non-diabetic individuals with 800 IU/day of vitamin E over 96 weeks. Beyond ALT, improvement was also noted in hepatic steatosis and inflammation, hepatocyte ballooning, and NASH activity score. Subsequent analysis of the PIVENS data confirmed that the benefits were irrespective of the weight loss, further substantiating the beneficial effects of vitamin E[51,52]. A meta-analysis by Sato et al[53] revealed significant improvement in hepatic biochemistry and histological changes in NASH treated with vitamin E. A 2022 phenome-wide association study identified protective benefits of vitamin E, most pronounced in overweight and diabetic patients, at doses exceeding 400 IU/day, and with an overall reduction in mortality[54]. Conversely, the TONIC trial, a multicenter study involving pediatric and adolescent subjects, failed to demonstrate a statistically significant improvement in hepatic chemistries[55]. Casting further shadows over prolonged vitamin E therapy, the SELECT trial reported an increased incidence of prostate cancer (Hazard ratio: 1.17; 99%CI: 1.004-1.36, P = 0.008) among men on vitamin E compared to those on placebo[56]. Considering the lack of convincing long-term data on the beneficial effects and concerns over prostate cancer, vitamin E is currently not recommended as a targeted therapy for MASH by the European Association for the Study of the Liver (EASL) practice guidelines, 2024[57]. The 2023 AASLD guideline states that vitamin E supplements can be considered in select individuals with NASH without diabetes mellitus; however, vitamin E lacks United States Food and Drug Administration (FDA) approval for use in NAFLD[58].

FXR agonists

Bile acids, whether primary or secondary, are the endogenous FXR ligands, with chenodeoxycholic acid being the most potent. The 6α-ethyl chenodeoxycholic acid, known as obeticholic acid (OCA), is a synthetic FXR agonist. The drug was approved in 2016 for use in primary biliary cholangitis (PBC) in patients without cirrhosis or with compensated cirrhosis, not responding or intolerant to ursodeoxycholic acid. However, post-marketing, pooled data analysis of patients with PBC treated with OCA also revealed a higher incidence of dose-dependent, serious hepatic complications, including decompensation and death. Hence, the FDA recommends against the use of OCA in decompensated cirrhosis as well as in patients with compensated cirrhosis with portal hypertension. In 2018, the drug received a black box warning regarding severe hepatotoxicity[59].

OCA was also used, off-label, in patients with primary sclerosing cholangitis and NASH. In 2015, the FLINT trial reported histologic improvement with OCA, including attenuation of steatosis, inflammation, and fibrosis in non-cirrhotic NASH[60]. The REGENERATE Phase III trial also demonstrated biochemical and histological improvement, as well as superior results with 25 mg daily compared to 10 mg dosing in pre-cirrhotic NASH[61]. The trials reported dose-dependent pruritus as the most frequent adverse effect, occurring in 23% of participants in FLINT and 51% in REGENERATE. The trials also reported reduced high-density lipoproteins (HDL) and high total and LDL cholesterol levels related to drug therapy. However, OCA was never approved for treating MASLD/MASH, despite multiple requests by the drug developer. Furthermore, in 2023, the FDA panel voted against using OCA in NASH, citing inadequate evidence and potential risks[62].

The newer FXR agonists in the pipeline include cilofexor, TERN-101, tropifexor, vonafexor, MET-409, and nidufexor. All these medications are in phase I or II trials, and available data reveal favorable impacts on hepatic biochemistry and histology. All these drugs report pruritus as a significant adverse effect but with fewer lipid disturbances. Further controlled trials and real-life data should confirm the beneficial effects of these promising classes of medications[63].

THR-β agonists

Resmetirom, a selective THR-β, was approved for human use in March 2024. The MAESTRO-NASH trial, a Phase III, multicenter, randomized controlled trial conducted across 15 countries, reported improved steatoinflammatory changes and fibrosis in patients with biopsy-proven NASH, with fibrosis scores ranging from F1b to F3. Resolution of NASH was reported in 25.9% of patients receiving 80 mg and 29.9% receiving 100 mg of resmetirom, compared to 9.7% in the placebo arm, at the end of 52 weeks. Improvement in fibrosis occurred in 24.2% and 25.9% of patients treated with 80 mg and 100 mg resmetirom, respectively, compared to 14.2% in the placebo group. However, those with no fibrosis and cirrhosis were excluded from the study[64]. A subsequent meta-analysis by Dutta et al[65] reported significant improvements in lipids, hepatic biochemistry, cytokeratin 18, and radiological parameters, including Fibroscan^® and magnetic resonance imaging-proton density fat fraction (MRI-PDFF). The MRI-PDFF reported a mean difference of -27.76% and -36.01% for 80 mg and 100 mg of resmetirom, respectively, suggesting a significant reduction in hepatic fat content. Firboscan reported a mean difference of -21.45 dBm with an 80 mg dose and -25.51 dBm with a 100 mg dose. The significant adverse effects reported in trials included gastrointestinal disturbances, such as diarrhea and nausea[66]. The ongoing MAESTRO-NASH-OUTCOMES and MAESTRO-NAFLD-OLE trials are expected to provide further insights into this groundbreaking medication regarding its role in compensated cirrhosis and long-term safety, respectively. Other selective THR-β agonists include sobetirome, eprotirome, and VK2809. Eprotirome trials were halted due to funding issues, according to the manufacturer, while sobetirome trials were halted due to concerns about hepatotoxicity, cartilage damage, and increased cardiovascular risk[67]. The phase IIb VOYAGE trial reported promising data with VK2809, again with no significant adverse effects[68].

PPAR agonists

PPARα agonists: This class of molecules includes the traditional fibrates: Fenofibrate, bezafibrate, gemfibrozil, and the novel selective agent, pemafibrate.

Conventional agents have proven benefits in hypertriglyceridemia and, to a lesser extent, in elevating HDL levels. While some studies demonstrate benefits with reduced liver enzymes and fat accumulation, the overall impact in patients with MASLD/MASH remains inconsistent and unclear[69,70]. Fibrates are myotoxic, especially in combination with statins or in those with impaired renal function. Fenofibrate has been associated with an increase in creatinine and a decline in glomerular filtration rates compared to placebo trials[71]. Pemafibrate, a selective PPARα modulator, is more effective in lowering triglyceride levels than other medications. In a 48-week trial involving patients with MASLD, pemafibrate significantly reduced liver enzymes and NAFLD fibrosis scores[72]. It appears to be better tolerated and safer than traditional fibrates, particularly in patients with kidney dysfunction.

PPARγ agonists: The thiazolidinedione class primarily focuses on glucose homeostasis through improved insulin sensitivity. They also positively affect lipid profiles by increasing HDL and lowering triglyceride levels. Pioglitazone and rosiglitazone, the molecules belonging to this family, are approved for the treatment of T2DM. Pioglitazone has demonstrated benefits in NASH, particularly in individuals with insulin resistance, with the attenuation of steatosis, inflammation, and even fibrosis in some cases[51,73]. Although the PIVENS study reported improvements in individual components of NAFLD/NASH, it failed to achieve the prespecified outcome in the trial and was found to be inferior to vitamin E[51]. Additionally, side effects like weight gain, fluid retention, and a higher risk of heart failure have limited its broader use. Thiazolidinediones are primarily metabolized in the liver and therefore require no dose adjustment in cases of renal dysfunction. Instead, they confer renoprotective effects through anti-inflammatory, antioxidant, and anti-apoptotic effects[74].

Dual PPARα/γ agonists: Saroglitazar activates both PPARα and PPARγ, thereby helping to reduce high triglyceride, total cholesterol, and LDL levels while also augmenting insulin sensitivity. The molecule has been evaluated to be safe and effective in diabetic dyslipidemia[75]. Trials with Saroglitazar reported improvement in transaminase levels, hepatic fat content, and NASH activity indices[76,77]. According to the drug manufacturer, Zydus, saroglitazar received approval from the Drug Controller General of India for the treatment of NASH in 2020; however, this information could not be verified from the Central Drugs Standard Control Organisation portal of the country[78,79]. Saroglitazar at a dose of 4 mg/day improves lipid and glycemic profile, transaminase levels, and liver stiffness[80]. The molecule is generally safe; however, possible side effects may include mild stomach upset, fluid retention, and weight gain, which are likely due to its partial action on PPARγ.

Pan-PPAR agonists: Lanifibranor activates PPAR α, γ, and δ; targets multiple aspects of MASH pathogenesis. It enhances fatty acid oxidation via PPAR-α, improves insulin sensitivity, and reduces inflammation via PPAR-γ while modulating lipid metabolism via PPAR-δ. The phase II NATIVE trial showed encouraging results, improving inflammation and fibrosis in people with NASH[81]. It also improved the glycemic and lipid profiles, with few adverse effects: Weight gain, peripheral edema, and anemia. The drug is undergoing Phase III NATiV3 clinical trials to evaluate its efficacy and safety. The Phase III trial was temporarily paused in February 2024 after a patient developed an unexpected elevation in liver enzymes; however, it continued and completed enrollment in April 2025, with results expected in late 2026[82,83].

GLP-1 agonists

GLP-1 is a gut-derived incretin, which, via increased insulin secretion coupled with attenuation of glucagon release and gastric emptying, induces satiety, promotes weight loss, and improves glucose-lipid homeostasis. This class of medication includes liraglutide, semaglutide, dulaglutide, exenatide, and tirzepatide, all of which are approved for the management of T2DM. All these molecules have been evaluated in MASLD/MASH, as insulin resistance, hyperlipidemia, and body mass index also play a role in the pathogenesis of steatotic liver diseases. The LEAN trial, in patients with biopsy-proven NASH, evaluated liraglutide at 1.8 mg/day vs placebo for 48 weeks. It reported NASH resolution in 39% of the liraglutide arm compared to 9% in the placebo group, with reduced progression of fibrosis[84]. Semaglutide has shown efficacy in resolving NASH in 59% of patients, compared to 17% in the placebo arm, in a phase 2 trial; however, improvement in fibrosis was not statistically significant[85]. Data from the REWIND trial suggest favorable hepatic outcomes with dulaglutide, particularly with a once-weekly dose, although it has yet to be evaluated in a dedicated NASH biopsy trial[86]. Klonoff et al[87] reported a reduction in hepatic fat content and transaminase levels in patients with NAFLD and diabetes with exenatide; again, histological evidence of improvement is limited. Tirzepatide, a dual agonist of GLP-1 and Glucose-dependent Insulinotropic Polypeptide (GIP), has demonstrated superior metabolic and hepatic effects compared to isolated GLP-1 agonists. In the SYNERGY-NASH trial, tirzepatide significantly reduced liver fat and improved non-invasive markers of liver inflammation[88].

Tirzepatide is more effective than semaglutide and liraglutide in terms of weight loss, glycemic control, and major adverse cardiac events; the same may be true for its efficacy in MASLD/MASH; however, there are very limited head-to-head comparisons available[89]. The additional benefits could be a result of the combined GLP1/GIP agonism. The meta-analysis by Luo et al[90] reported that semaglutide is superior to liraglutide and dulaglutide. To date, none of these agents have been approved for managing patients with MASLD/MASH despite promising results and a favorable safety profile.

SGLT-2 inhibitors

SGLT-2 inhibitors, a class of oral antidiabetic agents, have demonstrated hepatoprotective effects, making them yet another therapeutic option for patients with MASLD/MASH, especially those with T2DM. In the E-LIFT trial, empagliflozin was found to lower liver fat content, as assessed by MRI and liver enzymes, over 20 weeks in individuals with T2DM and NAFLD[91]. The EFFECT-II trial demonstrated meaningful reductions in liver fat content and improvements in insulin resistance and body weight with dapagliflozin, either alone or in combination with omega-3 fatty acids[92]. Similarly, a study by Arai et al[93] found that 48 weeks of SGLT-2 inhibitor therapy decreased transaminase levels, liver stiffness, and Fibrosis-4 index in patients with NAFLD. Although not yet explicitly approved for MASLD/MASH, the metabolic and hepatic improvements associated with SGLT2 inhibitors, along with their cardiovascular and renal benefits, make them a viable option, especially for patients with coexisting T2DM.

Other antidiabetic medications

Metformin, the only biguanide currently in clinical use, has a well-established safety and efficacy profile in T2DM, which has been demonstrated over more than five decades. It is believed to act by reducing hepatic glucose synthesis, increasing gut glucose utilization, increasing GLP-1 levels, and attenuating insulin resistance. The insulin-sensitizing effects of metformin have been explored in the treatment of MASLD/MASH, as insulin resistance plays a key role in its pathogenesis[94]. Several animal model studies report reduced hepatic fat content with metformin therapy; however, the beneficial effects on hepatic inflammation, oxidative stress, and fibrosis were inconsistent[94]. Clinical studies in patients with T2DM have reported a reduction in BMI and liver enzymes in those with NAFLD at doses of 1 g to 2 g per day[94-97]. Additionally, the use of metformin in combination with thiazolidinediones, GLP-1 agonists, SGLT-2 inhibitors, or dipeptidyl peptidase-4 inhibitors further augmented the beneficial effects[94,98,99]. Despite metabolic and biochemical improvements, trials and meta-analyses have largely failed to demonstrate significant histological improvements in steatosis, inflammation, or fibrosis in patients with NAFLD/NASH[100].

Insulin and insulin secretagogues: Physiologically, insulin inhibits lipolysis and promotes lipogenesis; therefore, it should be beneficial for fatty liver disease. Hyperinsulinemia is not the cause of fatty liver disease but rather the effect of insulin resistance. Neither insulin nor its secretagogues, sulfonylureas, significantly impact insulin sensitivity. Very few trials have explored the role of insulin therapy in MASLD/MASH, likely due to the theoretically counterproductive mechanism. In an animal model trial, utilizing NASH hamsters with streptozotocin-induced hyperglycemia, insulin therapy improved hyperglycemia, dyslipidemia, hepatic steatosis, inflammation, and fibrosis[101]. The fallacy of this study is that streptozotocin-induced DM by pancreatic β-cell toxicity is more similar to type 1 rather than T2DM. Fatty liver disease is a primary concern in T2DM and metabolic syndrome rather than in type 1 DM; hence, this data might not apply in clinical practice. Liu et al[102] reported improved liver fat content with insulin glargine in patients with NAFLD and T2DM, although to a lesser extent than with exenatide, in a randomized controlled trial. The addition of insulin glargine to oral hypoglycemic agents was associated with reduced hepatic fat measures, as estimated by magnetic resonance spectroscopy, in patients with T2DM[103]. On the contrary, patients with DM and fatty liver disease on insulin or sulfonylurea had a higher prevalence of advanced fibrosis on liver biopsy[104]. Limited data also exist suggesting an increased risk of hepatocellular carcinoma, irrespective of cirrhosis, in patients on insulin therapy[105]. Sulfonylureas and meglitinides are metabolized in the liver and carry a higher risk of hypoglycemia in patients with poor hepatic reserve. They are not recommended for patients with advanced liver disease[106]. Overall, the data is sparse in recommending or refuting insulin or its secretagogues from a pure fatty liver perspective.

Statins

Statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, a key enzyme in lipid metabolism, reduce in vivo cholesterol synthesis. They possess a wide range of hypolipidemic effects, reducing LDL by 25% to 60%, total cholesterol by 17% to 35%, and triglycerides by 10% to 40%, depending on the type and dose of statins[107,108]. Large-scale studies have reported a very high incidence of hypertriglyceridemia and hyperlipidemia in patients with MASLD and MASH, up to 60% to 80%[1,109]. Beyond their lipid-lowering effects, statins exhibit a multitude of impacts, collectively referred to as pleiotropic effects, including, but not limited to, anti-inflammatory, anti-proliferative, antioxidant, and anti-thrombotic effects, as well as attenuating effects on endothelial dysfunction and vascular remodeling[108]. Most of the effects, as mentioned earlier, play a role in the pathogenesis of MASLD/MASH, again supporting the use of statins in this group of patients. Statins are recommended for the primary and secondary prevention of cardiovascular disease by the American College of Cardiology and the American Heart Association. The reality that cardiovascular disease is the most common cause of mortality in MASLD/MASH further vouches for the role of statins in MASLD/MASH[110,111]. Having said this, statin hepatotoxicity has always been a concern for clinicians, especially while using the agent in patients with background liver disease.

Other novel agents

FGF21 analogs have been extensively evaluated for their antifibrotic and antisteatotic effects in the MASH model. Pegbelfermin was the first drug of this class to be assessed; however, it has largely fallen out of favor due to the failure to demonstrate significant histological improvement in the Phase IIb FALCON 1 and 2 trials[112,113]. Efruxifermin and pegozafermin belong to the same class and are undergoing phase III trials in patients with advanced fibrosis[114].

FGF19 analogs, Aldafermin and NGM282, are undergoing trials for the treatment of MASLD/MASH. FGF19 is a gut-derived, mostly ileal, hormone that interacts with the hepatic receptor FGFR4 to initiate many metabolic effects. It attenuates bile acid synthesis, regulates carbohydrate and lipid metabolism, and enhances β-oxidation, reducing oxidative stress and inflammation, ultimately leading to a favorable response to fatty liver disease. Rinella et al[115] reported a significant reduction in hepatic fibrosis in patients with compensated NASH cirrhosis following the administration of Aldafermin 3 mg for 48 weeks. A recent meta-analysis of four trials, including 491 patients, reported MASH resolution, improvement in fibrosis, and a reduction in hepatic fat fraction in biopsy-proven MASH, with a favorable safety profile. However, concerns exist regarding FGF19 and FGFR4 activation due to their potential links to cancers, including HCC[116].

Fatty acid synthase inhibitors block de novo lipogenesis, thereby attenuating lipotoxicity, inflammation, and subsequent fibrosis. Denifanstat, as reported in the recently concluded Phase IIb trial, FASCINATE-2, showed statistically significant improvements in NAFLD activity scores, NASH resolution, and fibrosis stage compared to placebo[117]. The positive results from the trial yielded Denifanstat, a breakthrough therapy designation from the FDA, for treating MASH with advanced fibrosis.

Rencofilstat, a non-immunosuppressive cyclophilin inhibitor, was evaluated in MASH and showed promising antifibrotic effects in Phase IIa trials[118]. The FDA granted Rencofilstat fast-track designation for treating NASH in 2021; however, the phase IIB trials were halted in 2024, citing resource constraints[119].

The galectin-3 inhibitor belapectin was found to reduce hepatic fibrosis and portal hypertension in preclinical trials, with a favorable safety profile in Phase 1 trials[120]. However, Phase IIb trials failed to reproduce the similar benefits observed over placebo[121].

Aramchol, a stearoyl-CoA desaturase inhibitor, has shown modest improvement in hepatic fibrosis and NASH resolution without significant adverse effects; however, it failed to demonstrate a favorable impact on hepatic fat content[122].

Acetyl-CoA carboxylase (ACC) inhibitors reduce hepatic de novo lipogenesis via the acetyl-CoA carboxylase 1 isoenzyme while enhancing mitochondrial fatty acid oxidation through the ACC2 isoenzyme. The net reduction in hepatic lipid load attenuates lipotoxicity, characterized by apoptosis, inflammation, and fibrosis. The first molecule of this class, Firsocostat, reported a median relative reduction in hepatic fat content of 29% compared to 8% in the placebo group. Paradoxically, the agent was associated with plasma hypertriglyceridemia in a subset of patients[123].

Other novel agents in the pipeline include a CC-chemokine receptor antagonist, Cenicriviroc; mitochondrial pyruvate carrier inhibitors, such as MSDC-0602K; a pan-caspase inhibitor, Emricasan; a lysyl oxidase-like 2 inhibitor, Simtuzumab; and patatin-like phospholipase domain-containing protein-3 targeting agents, including ION839 and LY3849891. Prebiotics, probiotics, and even fecal microbiota transplants have been explored in treating MASLD/MASH, targeting the gut microbiome alterations observed in these patients[124].

In summary, as of mid-2025, resmetirom is the only United States-FDA-approved medication for patients with MASH and moderate to advanced fibrosis, specifically stages F2 to F3. The AASLD practice guidance, 2023, states that the use of semaglutide and pioglitazone in the context of DM could benefit NASH, while vitamin E can be considered for patients without DM. However, none of these agents are approved by the United States FDA, and their use is rather off-label for MASLD/MASH[58]. The drug manufacturer of Saroglitazar in India claims that the molecule received approval for the treatment of NASH; however, the author(s) could not confirm this information[78,79]. Despite having an ample number of molecules in the pipeline for the management of MASLD/MASH, translating these into day-to-day clinical practice faces major hurdles due to genetic and ethnic patient heterogeneity, lack of validated non-invasive endpoints, limited long-term outcome data, safety concerns, and high costs. Many of these factors lead to regulatory uncertainties, further complicating the real-world application of these therapeutic molecules. An excerpt of candidate molecules, including their mechanism of action, therapeutic targets, and the phase of trials in the treatment of MASLD/MASH, is tabulated in Table 1.

Table 1 Pharamacotherapy of metabolic dysfunction-associated steatotic liver disease.

Class of medication	Mechanism of action/target(s)		Candidate medication	Phase of development notable trials
FXR agonists	Regulates bile acid metabolism; Reduces insulin resistance; Reduces hepatic lipogenesis, inflammation, fibrosis		Obeticholic acid	Phase 3 (REGENERATE)
			Tropifexor	Phase 2 (FLIGHTFXR)
			Cilofexor	Phase 2
PPAR agonists	Increased clearance of intrahepatic fat; Improves insulin sensitivity; Downregulates stellate cells; Attenuates fibrogenesis	Pan PPAR-α/δ/γ	Lanifibranor	Phase 3 (NATiV3)
		Dual PPAR-α/δ	Elafibranor	Phase 3 (RESOLVE-IT)
		Dual PPAR-α/γ	Saroglitazar	Phase 2b
THR-βagonists	Reduce hepatic triglycerides by enhanced intrahepatic lipolysis, lipophagy, β-oxidation, and bile acid synthesis		Resmetirom	Phase 3 (MAESTRO-NASH)
			VK2809	Phase 2b (VOYAGE)
GLP-1 agonists	Induces satiety, weight loss; Incretin effect: Improved glycemic control; Positive effects lipid metabolism		Semaglutide	Phase 3 (ESSENCE)
			Liraglutide	Phase 2 (LEAN)
SGLT2 inhibitors	Improves glycemic control, lipid profile; Weight loss; Postulated anti-inflammatory/antifibrotic effects		Dapagliflozin	Phase 3 (DEAN), Phase 4
			Empagliflozin	Phase 4
Galectin-3 inhibitors	Reduce macrophage-mediated inflammation; Inhibits activation and proliferation of stellate cells; Reduces hepatocyte apoptosis, promotes regeneration		Belapectin	Phase 3 (NAVIGATE)
			Selvigaltin	Phase 1b/2a (GULLIVER-2)
FGF analogues	Decreases hepatic fat content; Improves insulin sensitivity; Anti-inflammatory, antifibtotic effects	FGF21	Pegbelfermin	Phase 2b
		FGF19	Aldafermin	Phase 2b (ALPINE)
ACC inhibitors	Decreses de novo lipogenesis; Promotes fatty acid oxidation		Firsocostat	Phase 2
MPC inhibitors	Inhibits pyruate transport from cytosol to mitocondria		MSDC-0602K	Phase 2b (EMMINENCE)
	Decreases de novo lipogeneis, Increases fatty acid oxidation		PXL065	Phase 2 (DESTINY-1)
CCR2/CCR5 antagonist	Anti-inflammatory, antifibrotic effects		Cenicriviroc	Phase 3 (AURORA)
Cyclophiphin inhibitor	Regulates collagen and extracellular matrix; Antisteatotic, anti-inflammatory, antifibrotic effects		Rencofilstat	Phase 2b (ASCEND-NASH)
Pan-caspase inhibitor	Anti-apoptotic, anti-inflammatory effects		Emricasan	Phase 2 (ENCORE-NF)
SCD1 inhibitor	Prevents hepatic triglyceride synthesis		Aramchol	Phase 3 (ARMOR)
LOXL2 inhibitor	Impedes collagen cross linking, fibrosis progression		Simtuzumab	Phase 2
siRNA	Silencing effects of interfering RNA on metabolic pathways, inflammation, callagen synthesis, fibrosis, etc.		GalNAc-siPLIN2	Preclinical
			ALN-HSD	Phase 1/2
			BMS986263	Phase 2
FASN inhibitor	Inhibits de novo hepatic lipogenesis		Denifanstat	Phase 2b (FASCINATE-2)
Vitamin E	Antioxidant action: Reduces hepatic oxidative stress/injury		Vitamin E	Phase 3 (PIVENS; TONIC)
Statins	HMG-CoA reductase inhibitor - blocks cholestrol biosynthesis; Pleomorphic effects: Anti-inflammatory, antifibtotic		Atorvastatin	Phase 2/3

CONCLUSION

Pharmacotherapy for MASLD/MASH, formerly NAFLD/NASH, is rapidly evolving, with multiple agents demonstrating promise in targeting diverse pathogenic pathways, including metabolic dysregulation, inflammation, and fibrosis. Resmetirom, a selective THR-β agonist, is the only agent currently approved for the treatment of MASH. Off-label therapy with vitamin E, obeticholic acid, GLP-1 analogs, SGLT-2 inhibitors, and PPAR agonists has met with inconsistent or unconfirmed benefits. The heterogeneity of MASH pathophysiology necessitates a personalized, mechanism-driven approach to treatment, integrating metabolic, endocrine, and hepatologic perspectives. Continued translational research and large-scale trials will be critical to establishing standardized, evidence-based pharmacotherapy in patients with MASLD/MASH.