Hepatic thyroid hormone receptor beta (THR-β) plays an important role in lipid homeostasis, including the regulation of lipoprotein, triglyceride, and cholesterol metabolism^[9,10]. Resmetirom, a selective THR-β agonist, became the first drug in March 2024 to receive accelerated approval from the Food and Drug Administration (FDA) for adults with MASH and fibrosis (stages F2-F3). Dosing is weight-based, with 80 mg administered once daily in individuals weighing < 100 kg and 100 mg once daily in those ≥ 100 kg^[11].

This approval was based on the results of the MAESTRO-NASH trial, which included patients with MASH and fibrosis stage F1-F3, and compared resmetirom (80 and 100 mg) with placebo over 52 weeks. Resmetirom was superior in achieving MASH resolution without worsening of fibrosis, with response rates of 25.9% and 29.9% with the 80 and 100 mg doses, compared with 9.7% in the control group. It also demonstrated a benefit in improving fibrosis, with rates of 24.2%, 25.9%, and 14.2%, respectively^[12]. This drug has an acceptable safety profile, with most adverse events being mild and self-limited^[13]. Additional trials are ongoing to evaluate its efficacy and safety, including NCT04951219 and NCT05500222.

Incretin-based therapies have become an important therapeutic strategy for MASLD/MASH in recent years, given their ability to improve hepatic outcomes while also providing metabolic, cardiovascular, and renal benefits.

In August 2025, semaglutide received FDA accelerated approval for noncirrhotic MASH with moderate-to-advanced fibrosis (F2-F3)^[14]. The ESSENCE trial, which included 800 patients with MASH and fibrosis (stages F2-F3), demonstrated that treatment with subcutaneous semaglutide 2.4 mg given once weekly over a 72-week period was superior to placebo in achieving histological resolution of MASH without worsening of fibrosis, with rates of 62.9% and 34.3%, respectively, and improvement in at least one stage of fibrosis without worsening of MASH, with rates of 36.8% vs. 22.4%^[15]. Additionally, among secondary outcomes, 32.7% of patients achieved both, compared with 16.1% in the placebo group^[15]. The ongoing phase of the ESSENCE trial is evaluating the effects on liver-related outcomes over a 240-week period. The treatment is generally well tolerated, with most adverse events being gastrointestinal, which are generally mild. Candidates for this therapy include patients with MASH and fibrosis stages F2-F3, who may be identified using noninvasive tests (NITs), given that liver biopsy is invasive and often unnecessary; however, it is not approved for patients with cirrhosis^[16].

From a therapeutic positioning perspective, resmetirom and semaglutide represent complementary approaches for patients with noncirrhotic MASH and F2-F3 fibrosis. Resmetirom is a liver-directed THR-β agonist that acts primarily by improving hepatic lipid metabolism and also favorably affects the atherogenic lipid profile^[12]. In contrast, semaglutide is a systemic GLP-1 receptor agonist that promotes substantial weight loss and improves glycemic and cardiometabolic control^[15]. Both agents have demonstrated MASH resolution and fibrosis improvement in placebo-controlled phase 3 trials^[12,15]; however, no head-to-head trial has directly compared their efficacy or safety. Therefore, cross-trial differences in response rates should be interpreted cautiously. In clinical practice, resmetirom may be particularly relevant when significant fibrosis and dyslipidemia predominate, whereas semaglutide may be especially attractive in patients with obesity, type 2 diabetes, or a high cardiometabolic burden. Treatment selection should also consider route of administration, adverse-effect profile, contraindications, patient preference, and access.

Other incretin-based therapies, such as tirzepatide [GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonist] or survodutide (GLP-1/glucagon agonist), have shown preliminary data supporting metabolic improvement but currently lack FDA approval for liver-specific indications.

The SYNERGY-NASH trial enrolled 190 patients with biopsy-confirmed MASH and moderate-to-advanced fibrosis. Participants received subcutaneous tirzepatide once weekly at doses of 5, 10, or 15 mg, or placebo for 52 weeks. Tirzepatide was superior to placebo at all studied doses in achieving MASH resolution without worsening of fibrosis; response rates were 44%, 56%, and 62% in the 5, 10, and 15 mg groups, respectively, compared with 10% in the control group. Improvement in fibrosis without worsening of MASH was observed in 55%, 51%, and 51% of patients receiving 5, 10, and 15 mg, compared with 30% in the control group^[17]. Patients receiving tirzepatide achieved a mean weight reduction of approximately 15%. Most adverse events were gastrointestinal and generally mild to moderate. Despite promising results, the FDA has approved this drug only for diabetes and obesity, but not for MASH, as more trials are needed to evaluate its safety and efficacy for this disease.

Other agents, such as survodutide and pemvidutide, have been investigated in patients with MASH. In a trial including 293 adults with MASH and liver fibrosis (F1-F3), subcutaneous survodutide at 2.4, 4.8, and 6.0 mg doses was compared with placebo. All doses were more effective than placebo in improving MASH, with response rates of 47% at 2.4 mg, 62% at 4.8 mg, and 43% at 6 mg, vs. 14% in the control group. Fibrosis improved by at least one stage in 34%, 36%, and 34% of patients, respectively, vs. 18% in the placebo group. A reduction of at least 30% in liver fat was observed in 63% of individuals receiving 2.4 mg, 67% receiving 4.8 mg, and 57% receiving 6.0 mg, vs. 14% in the control group^[18]. However, adverse events were more frequent and led to treatment discontinuation in approximately 20% of patients.

In the phase 2b IMPACT trial, once-weekly subcutaneous pemvidutide at doses of 1.2 and 1.8 mg was evaluated in subjects with MASH and liver fibrosis F2-F3. At week 24, pemvidutide was superior to placebo in achieving MASH resolution without worsening of fibrosis; however, no statistically significant improvement in fibrosis was observed. Follow-up through week 48 is ongoing to determine its potential long-term antifibrotic effects. Pemvidutide demonstrated a favorable safety and tolerability profile, with treatment discontinuation reported in only 1% of patients^[19].

Phase 3 trials are required to generate more comprehensive data on efficacy and safety.

Triple agonist agents are being studied as potential therapies for MASLD and MASH, particularly retatrutide and efocipegtrutide. In a recent trial that included 98 patients with MASLD, subcutaneous retatrutide administered once weekly for 48 weeks reduced liver fat content. Mean relative change from baseline in liver fat at 24 weeks was -42.9% with 1 mg, -57% with 4 mg, -81.4% with 8 mg, and -82.4% with 12 mg, compared with +0.3% in the placebo group. In addition, normalization of liver fat content was observed in 27% of patients receiving 1 mg, 52% with 4 mg, 79% with 8 mg, and 86% with 12 mg, compared with 0% in the control group^[20]. Adverse events were more common at higher doses (8 and 12 mg). More studies are necessary to determine efficacy and safety; however, it appears to be a promising therapeutic option.

A phase 2 clinical trial (NCT04505436) is ongoing to evaluate the safety and efficacy of efocipegtrutide over 12 months in subjects with MASH.

Peroxisome proliferator-activated receptors (PPARs; α, β/δ, and γ) are a group of nuclear receptors that modulate key inflammatory and fibrogenic pathways, as well as lipid and glucose metabolism, all of which determine MASLD and MASH progression^[21]. Some PPARγ and pan-PPAR agonists benefit liver steatosis and fibrosis.

Pioglitazone (PPARγ agonist) improves hepatic steatosis. A meta-analysis of five clinical trials including patients with MASH demonstrated that pioglitazone, at doses of 30 to 45 mg daily, was related to MASH resolution [odds ratio (OR) 3.22, 95% confidence interval (CI) 2.17-4.79] and fibrosis improvement (OR 1.66, 95%CI: 1.12-2.47), irrespective of the presence of type 2 diabetes^[22]. However, in the absence of large-scale trials, current international guidelines do not recommend pioglitazone as a MASH-targeted therapy, although it may be considered as a treatment option in selected patients.

Another agent in this class is lanifibranor (pan-PPAR agonist). In the NATIVE trial, which included patients with MASH, lanifibranor was administered at doses of 800 mg or 1,200 mg daily and compared with placebo. Patients receiving 1,200 mg achieved higher rates of MASH resolution (49% vs. 22%) and fibrosis improvement (48% vs. 29%) than those receiving placebo^[23]. Liver enzyme levels, lipids, and inflammatory biomarkers improved in the lanifibranor groups. Most adverse events were self-limited, with a dropout rate of less than 5%, which was consistent across the trial groups. The NCT04849728 trial is currently evaluating its efficacy and safety in MASH with fibrosis stages F2-F3 over 72 weeks of treatment.

SGLT2 inhibitors are linked to reductions in adverse liver-related events^[24]. A recent study including adults with MASH demonstrated that dapagliflozin 10 mg once daily for 48 weeks was superior to placebo in achieving resolution of MASH, with rates of 23% vs. 8% in the control group [risk ratio (RR) 2.91; 95%CI: 1.22-6.97], as well as in reducing fibrosis, observed in 45% in the intervention group compared with 20% in the placebo (RR 2.25; 95%CI: 1.35-3.75; P = 0.001)^[25]. However, these agents are not approved for liver-directed therapy and are currently used off-label for MASLD/MASH. Given their established indications for the treatment of type 2 diabetes, chronic kidney disease, and heart failure, they are unlikely to undergo dedicated phase 3 clinical trials specifically for MASLD/MASH. Nevertheless, their use may be considered in patients with MASLD when indicated for other comorbid conditions.

FGF21 is a key hormone involved in regulating and maintaining lipid and glucose metabolism. Several FGF21 analogues, such as pegozafermin and efruxifermin, are under investigation for the treatment of MASH, including in patients with compensated cirrhosis, with promising outcomes^[26].

In a study of subcutaneous pegozafermin administered for 24 weeks in 219 patients with MASH and fibrosis (F2 or F3), resolution of MASH was observed in 37% of patients receiving 15 mg weekly, 23% with 30 mg weekly, and 26% with 44 mg every two weeks, vs. 2% in the control group. Additionally, improvement in fibrosis was reported in 22%, 26%, and 27% of patients receiving 15 mg, 30 mg, and 44 mg, respectively, compared with 7% in the placebo group^[27].

The HARMONY trial included 128 subjects with MASH and fibrosis stages F2-F3, who were randomized to receive subcutaneous efruxifermin at doses of 28 mg or 50 mg weekly, or placebo. At week 24, improvement in fibrosis was observed in 39% of patients receiving 28 mg (RR 2.3; 95%CI: 1.1-4.8) and 41% of those receiving 50 mg (RR 2.2; 95%CI: 1.0-5.0), compared with 20% in the control group^[28].

More recently, the SYMMETRY trial evaluated treatment with efruxifermin 50 mg weekly in patients with MASH-related compensated cirrhosis (biopsy-confirmed stage F4 fibrosis). At week 36, 19% of patients receiving efruxifermin showed at least a 1-stage improvement in fibrosis compared with 13% receiving placebo, although this difference did not reach statistical significance. However, as a secondary outcome assessed at week 96, fibrosis improvement was observed in 29% of patients treated with efruxifermin vs. 11% of those receiving placebo, representing a greater numerical difference^[29]. These findings suggest that fibrosis regression may be a more prolonged process in patients with F4 fibrosis or compensated cirrhosis, likely reflecting the more advanced architectural distortion of the liver, as cirrhosis represents a distinct stage of the disease in which fibrosis reversal is inherently more difficult than in earlier stages. Therefore, the antifibrotic efficacy observed in patients with F2-F3 fibrosis should not be directly extrapolated to those with more advanced disease, highlighting the need for long-term clinical trials specifically designed for this population.

Other trials of efruxifermin (NCT06215716) and pegozafermin (NCT06318169) in patients with MASH are currently in progress to provide more evidence on safety and efficacy.

For many years, vitamin E has been widely used as a possible treatment for MASH, as supplementation has demonstrated antioxidant effects and histological improvement, particularly in patients without diabetes or cirrhosis. In a multicenter, randomized controlled trial, treatment with 800 IU of natural vitamin E (RRR-α-tocopherol) for 96 weeks reduced steatosis and hepatic inflammation, with no improvement in fibrosis^[30]. Although no antifibrotic benefit has been established, international guidelines provide a conditional recommendation, based on low-quality evidence, that vitamin E may be considered for selected patients with MASH without diabetes. However, high-dose vitamin E has been associated with potential risks, including hemorrhagic stroke, cardiovascular events, and prostate cancer^[31].

Statins have also been evaluated in patients with MASLD/MASH, with observational studies suggesting reductions in liver-related events and fibrosis progression^[32]. However, no consistent benefits in fibrosis regression have been demonstrated, and their efficacy in patients with MASH and fibrosis remains uncertain because no controlled trials have evaluated histological outcomes. For this reason, statins are not considered a targeted therapy for MASLD/MASH, and their use is recommended in patients with associated comorbidities, such as dyslipidemia or cardiovascular disease^[33,34].

Additional agents are in preclinical development, including fatty acid synthase inhibitors targeting de novo lipogenesis and profibrogenic pathways; diacylglycerol acyltransferase 2 (DGAT2) antisense inhibitor, which lowers hepatic and circulating triglyceride levels by downregulating lipogenic gene expression; and transglutaminase 2 inhibitors, which may prevent cell death, inflammation, and autophagosome maturation^[35-37].

The currently approved and emerging pharmacological therapies for MASLD/MASH are summarized in Table 2^[38-41].

The recent expansion of the therapeutic landscape has highlighted an important limitation of single-agent approaches. Because MASLD/MASH results from the interaction of metabolic, inflammatory and fibrogenic pathways, simultaneous modulation of multiple targets has emerged as a promising therapeutic strategy that may provide greater clinical benefit than isolated interventions; however, this remains under clinical evaluation^[41].

Although evidence regarding histological liver outcomes remains limited, the combination of pioglitazone and GLP-1 receptor agonists has gained interest because of its favorable effects on insulin resistance, body weight, hepatic steatosis, and overall cardiometabolic risk^[42].

From a mechanistic standpoint, this approach is particularly attractive, as pioglitazone favorably modulates glucose and lipid homeostasis and has been shown to induce resolution of steatohepatitis, with fibrosis improvement reported in some clinical trials, while GLP-1 receptor agonists promote weight loss and improve systemic metabolic control. Furthermore, combination therapy with pioglitazone and GLP-1 receptor agonists has been reported to be safe and effective for glycemic management while also reducing hepatic steatosis, suggesting a potential additive benefit in individuals with MASLD, although evidence demonstrating superior histological outcomes compared with monotherapy remains limited^[42].

Comparative analyses across contemporary clinical trials suggest that therapies targeting distinct biological pathways may provide complementary benefits. Among currently available approaches, FGF21 analogues (e.g., pegozafermin), incretin-based therapies (e.g., survodutide and tirzepatide), and THR-β agonists (e.g., resmetirom), consistently rank among the most effective interventions for achieving histological improvement^[43].

Notably, combination regimens such as cilofexor plus firsocostat ranked among the most effective interventions for fibrosis improvement, with this combination achieving a high surface under the cumulative ranking curve (SUCRA) ranking (71.38), second only to pegozafermin for fibrosis regression without worsening of MASH^[43]. These findings suggest that multi-target approaches may offer complementary therapeutic effects and that modulation of systemic metabolism may be particularly impactful; however, they should be interpreted cautiously until confirmed in randomized clinical trials. Moreover, the heterogeneity in mechanisms and treatment responses observed across agents supports further investigation of combination strategies, as single-pathway interventions may be insufficient to fully address the complex pathophysiology of MASH^[43].

Early clinical trial data further reinforce this concept. A phase 2 trial evaluating semaglutide alone or in combination with the farnesoid X receptor agonist cilofexor and/or the acetyl-CoA carboxylase inhibitor firsocostat in patients with nonalcoholic steatohepatitis (NASH) and F2-F3 fibrosis demonstrated that combination regimens were well tolerated and associated with greater reductions in hepatic steatosis, improvements in liver biochemistry, and favorable changes in noninvasive fibrosis markers compared with semaglutide monotherapy, despite similar weight loss across groups^[44]. These findings suggest that the hepatic benefits of combination therapy are not solely driven by weight reduction but rather by complementary mechanisms targeting metabolic dysfunction, bile acid signaling, and de novo lipogenesis. Similarly, the phase 2b ATLAS trial in 392 patients with advanced fibrosis or compensated cirrhosis (F3-F4) showed that although the primary endpoint of fibrosis improvement without worsening of NASH was not met, the combination of cilofexor and firsocostat demonstrated a numerical trend toward greater fibrosis improvement compared with monotherapy (21% vs. 12%), along with significant improvements in NASH activity and exploratory antifibrotic signals based on machine learning-assisted histologic assessment and noninvasive markers^[45]. Together, these studies suggest that combination strategies may yield broader biological effects than monotherapy, even without statistically significant primary endpoints. However, most available data derive from phase 2 studies, and no combination regimen has yet demonstrated sufficient evidence to support routine clinical use.

Additional combination regimens are also under active investigation. A phase 2 study evaluating ervogastat (a DGAT2 inhibitor) in combination with clesacostat (an acetyl-CoA carboxylase inhibitor) met a composite primary endpoint at 48 weeks, including MASH resolution without worsening of fibrosis and/or improvement in fibrosis without worsening of MASH. However, while the combination improved MASH resolution compared with placebo, it did not demonstrate superiority for fibrosis improvement alone, underscoring the ongoing challenge of achieving consistent antifibrotic efficacy^[46].

Despite these promising data, current clinical guidelines remain cautious. Global consensus recommendations emphasize individualized treatment selection based on fibrosis stage and cardiometabolic profile, recommending agents such as resmetirom or semaglutide as first-line options in selected patients, while not endorsing upfront combination therapy due to the lack of robust evidence. Instead, a sequential approach - adding therapies in cases of suboptimal response - is considered reasonable^[47]. Similarly, the 2024 AASLD Practice Guidance highlights the efficacy of resmetirom based on the MAESTRO-NASH trial but underscores that a substantial proportion of patients do not achieve histologic response and that evidence is insufficient to guide concomitant therapies^[48]. Overall, these considerations support a tailored therapeutic approach that incorporates stage, cardiometabolic profile, treatment response, approved indications, and the potential role of sequential or combination therapies^[46].

Several pharmacological agents have been evaluated for the treatment of MASLD/MASH; however, their use is not recommended because of either lack of efficacy or safety concerns. Among the most extensively studied agents that failed to demonstrate significant histological improvement are metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, omega-3 fatty acids, and elafibranor^[49]. Among therapies discontinued because of safety concerns, obeticholic acid is a notable example. In the REGENERATE trial, obeticholic acid demonstrated fibrosis improvement without worsening of MASH^[50]; however, its development was ultimately discontinued because of concerns regarding drug-induced liver injury, as well as its association with significant pruritus and increased low-density lipoprotein cholesterol levels.

Despite years of research, only two agents have been approved for the treatment of MASLD/MASH, underscoring the complex and multifactorial pathophysiology of the disease. The failure of several investigational agents has provided important lessons for the field, highlighting the limitations of targeting a single pathogenic pathway, the need for clinically meaningful endpoints beyond biochemical improvement, the importance of balancing efficacy with safety, and the value of improved patient stratification. Collectively, these insights support the continued development of novel antifibrotic therapies while emphasizing the importance of simultaneously addressing the metabolic comorbidities that drive disease progression.