Described as a clinical-histopathological definition in 1980, nonalcoholic steatohepatitis (NASH) [1], now renamed metabolic dysfunction-associated steatohepatitis (MASH) [2], has remained a neglected area for drug development for decades. Beyond hepatology, MASH is a systemic condition involving liver-related issues (such as fibrosis, cirrhosis, liver failure, hepatocellular carcinoma, and liver transplantation), metabolic complications (like type 2 diabetes), and extrahepatic consequences (including cardiovascular disease, chronic kidney disease, and extrahepatic cancers) [3–8]. Furthermore, MASH has a high global prevalence [9, 10]. The systemic nature and widespread prevalence of MASH have led to significant economic burdens, with costs reaching $222.6 billion in the USA in 2017 and up to €19.5 billion in Europe, encompassing both direct (medical care, diagnostic procedures, drugs, hospitalization) and indirect costs (loss of productivity, reduced quality of life, morbidity, and mortality) [11, 12].

In 2024, resmetirom became the first drug licensed for use in the USA and was subsequently approved by the European Medical Agency (EMA) for the same indication in Europe in August 2025. These regulatory bodies made their decisions based on published evidence showing the superiority of both the 80 mg and 100 mg doses of resmetirom over placebo in resolving NASH and improving liver fibrosis by at least one stage [13]. In August 2025, the Food and Drug Administration (FDA) also approved semaglutide for the treatment of MASH with moderate or advanced fibrosis [14] based on the results of a published trial [15].

In addition to resmetirom and semaglutide, other drugs are currently being evaluated in the field of MASH, as shown in Table 1. Drugs such as tirzepatide [16], denifanstat [17], dapagliflozin [18], and efruxifermin [19] have demonstrated efficacy in placebo-controlled double-blind, randomized clinical trials. What is common among these drugs? Table 2 highlights the significant diversity in chemical structures and mechanisms of action among these drugs, with resmetirom being the only agent approved for use in MASH in both the USA and Europe, alongside other promising drugs that have shown potential benefits in improving liver histology outcomes.

Taken collectively, recent studies summarized in Table 1, along with the heterogeneous mechanisms of action of these drugs illustrated in Table 2 and Figure 1, clearly document the notion that the pathogenesis of MASH involves both hepatic.

Additionally, MASH pathomechanisms exhibit substantial inter-individual variability [24, 25], paving the way for precision medicine approaches aiming to offer the right drug to the right person at the right moment (Figure 2) [26, 27].

The lesson from MASH drug trials is that there seem to be numerous different therapeutic targets. This concept opens the door to investigating other yet unexplored pathways involved in metabolic dysfunction-associated steatotic liver disease (MASLD) development. Future research should be developed along different trajectories. First, we need to identify and validate robust disease biomarkers that characterize distinct and homogeneous patient populations. MASH drugs should be utilized based on patient-specific pathogenesis. For example, patients need to be characterized along macro domains such as sex. Data indicating that sex may influence MASH continue to accumulate [28], and these sex discrepancies lay the foundation for sex- and reproductive-status specific analysis of trials [29, 30]. Moreover, specific gene variants may also require distinct drug approaches [31–33]. Additionally, it will be important to study in increasing detail how novel MASH drugs impact not only the molecular pathways involved but also the cellular bases of MASH [34]. Finally, while available drugs address certain molecular targets and pathways, innovative MASH drugs modifying different pathways and targets remain to be investigated (Figure 1).

These comprise the prospect of MASH treatment regarding i) the gut microbiota, ii) skeletal muscle, and iii) visceral adipose tissue.

The abundance of different drug options in the MASH arena, rather than a limitation, potentially offers additional advantages in the context of combination therapy. Drugs with different mechanisms of action may be rationally utilized with the aim of reducing doses and side effects of each drug class while maximizing the therapeutic benefit [42]. In this regard, areas in need of further investigation include the combined utilization of GLP-1 RA with fibroblast growth factor (FGF) analogues or antifibrotic agents [43]. Additionally, although the regulatory approval of combination therapy remains challenging [43], the association of currently available drugs that restore normal metabolic function (e.g., traditional antidiabetic, lipid-lowering drugs, anti-hypertensives, and antioxidants), with MASH-specific drugs represents an arena of potentially great significance. Approaches addressing the specific pathomechanisms involved in the individual patient promise to correct the underlying driving force of MASH [44].

A final consideration regards the financial and ethical sustainability of increasingly expensive drug approaches that some areas of the world have to utilize to combat the deleterious effects of unhealthy lifestyle habits on liver health [21, 45, 46], while other countries still struggle against famine and intermittent access to food [47].

The landscape of drug treatment for MASH is rapidly evolving, with two licensed drugs, resmetirom and semaglutide, and a growing array of additional therapeutic options demonstrating promising efficacy. The diverse mechanisms of action among agents such as tirzepatide, denifanstat, semaglutide, dapagliflozin, and efruxifermin highlight the complexity of MASH pathogenesis and the need for tailored treatment approaches. As we advance our understanding of these therapies and their clinical implications, it is crucial to balance the potential benefits with the risks of over-treatment. Ideally, all stakeholders should be involved in future studies, namely, investigators, patients, regulatory agencies, and industry [48]. Future research should focus on identifying patient-specific biomarkers, measuring portal pressure when clinically indicated, and optimizing combination therapies to enhance outcomes while minimizing adverse effects. Ultimately, a precision medicine approach will be essential in navigating this multifaceted condition and improving patient care in MASH management.