Hepatic thyroid hormone receptor‐β signalling: Mechanisms and recent advancements in the treatment of metabolic dysfunction‐associated steatohepatitis DOI
Stergios A. Pοlyzos, Giovanni Targher

Diabetes Obesity and Metabolism, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 10, 2024

The pharmacotherapy of metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, the steatohepatitis (MASH), remains a hot topic in research largely unmet need clinical practice. As first approval disease-specific drug, resmetirom, was regarded as milestone for management this common disease, comprehensive updated review aimed to highlight importance hepatic thyroid hormone (TH) receptor (THR)-β signalling treatment MASH, with special focus on resmetirom. First, genomic non-genomic actions liver-directed THR-β mediated mechanisms are summarized. has key role lipid carbohydrate metabolism; disruption leads dysmetabolism, thus promoting MASLD possibly progression MASH cirrhosis. In setting, is translated into significant association between primary hypothyroidism MASLD, confirmed by recent meta-analyses. An subclinical intrahepatic (i.e. state relatively low triiodothyronine concentrations, circulating TH concentrations within normal range) also emerging under investigation. line this, favourable results phase 3 placebo-controlled MAESTRO trials led conditional resmetirom US FDA treating adults moderate-to-advanced fibrosis. This opened new window burdensome bringing global scientific community front perspectives challenges.

Language: Английский

Resmetirom and thyroid hormone receptor‐targeted treatment for metabolic dysfunction‐associated steatotic liver disease (MASLD) DOI Creative Commons

Chang‐Hai Liu,

Qingchun Zeng, Tianxiao Hu

et al.

Portal hypertension & cirrhosis, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Abstract Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a rapidly increasing chronic worldwide, particularly among patients with type 2 diabetes. Its severe form, metabolic steatohepatitis (MASH), also on the rise. The treatment of MASLD and MASH poses significant challenges. Thyroid hormones their receptors thyroid hormone receptor (TR) agonists, especially resmetirom, have shown potential in improving metabolism reducing inflammation. play crucial role regulating maintaining physiological balance. However, MASLD, there reduced conversion 3,3′,5,5′‐tetraiodo‐ l ‐thyronine (T 4 ) to biologically active 3,5,3′‐triiodo‐ 3 ), resulting decreased T levels impaired hepatic TR signaling. This hormonal imbalance associated disrupted lipid metabolism. Resmetirom, an oral selective agonist that specifically targets hepatocytes, was approved by Food Drug Administration (FDA) March 2024 for moderate fibrosis non‐cirrhotic adults MASH. approval based results MAESTRO clinical program, which includes multiple‐stage research designs such as MAESTRO‐NASH, MAESTRO‐NAFLD‐1, MAESTRO‐NAFLD‐OLE, MAESTRO‐NASH‐OUTCOMES, aims evaluate efficacy safety resmetirom different populations patient. Although represents milestone MAFLD MASH, many questions remain regarding its long‐term effectiveness impact outcomes. Ongoing research, through holds promise providing additional insights into management using other similar medications.

Language: Английский

Citations

1
Roles of extracellular vesicles from different origins in metabolic-associated fatty liver disease: progress and perspectives DOI Creative Commons
Xinyi Wang, Sônia Nair Báo, Qi An

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 10, 2025

Metabolic-Associated Fatty Liver Disease (MAFLD) is the most common chronic liver disease worldwide, associated with systemic metabolic dysregulation. It can progress from simple hepatic steatosis (MAFL) to more severe conditions like Steatohepatitis (MASH), fibrosis, cirrhosis, and Hepatocellular Carcinoma (HCC). There a critical lack of reliable non-invasive diagnostic methods effective pharmaceutical treatments for MAFLD/MASH, emphasizing need further research. Extracellular vesicles (EVs) are nanoscale structures that play important roles in cell signaling by delivering bioactive molecules. However, there significant gap literature regarding EVs hosts, plants, microbiota MAFLD. This review explores potential various sources—host, microbiota—as biomarkers, therapeutic agents, drug carriers, treatment targets Firstly, host-derived extracellular MAFLD, focus on cell-type specific their components—proteins, miRNAs, lipids—for diagnosis monitoring were discussed. Moreover, it highlighted mesenchymal stem (MSC)-derived reducing lipid accumulation injury, immune cell-derived mitigating inflammation fibrosis. The also discussed use as carriers due ability deliver molecules impact mechanisms. Additionally, summarized research plant-derived EVs, which help reduce accumulation, inflammation, enhance gut barrier function Also, explored microbial-derived novel targets, particularly relation insulin resistance, dysfunction Overall, exploring diverse host, plant, sources this offers valuable insights into biomarkers strategies, could pave way options increasingly prevalent disease. Notably, challenges translating clinical practice thoroughly discussed, aiming provide possible directions strategies future

Language: Английский

Citations

1
Metabolic Dysfunction-Associated Steatotic Liver Disease: An Overview of Pharmacotherapy DOI
Mohamed Toufic El Hussein,

Daniel Favell

The Journal for Nurse Practitioners, Journal Year: 2025, Volume and Issue: 21(2), P. 105273 - 105273

Published: Feb. 1, 2025

Language: Английский

Citations

0
Novel drugs approved by the EMA, the FDA and the MHRA in 2024: A year in review DOI Creative Commons
Stavros Topouzis, Andreas Papapetropoulos, S P H Alexander

et al.

British Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Abstract In the past year, European Medicines Agency (EMA), Food and Drug Administration (FDA) Healthcare Products Regulatory (MHRA) authorised 53 novel drugs. While 2024 harvest is not as rich in 2023, when 70 new chemical entities were approved, number of ‘orphan’ drug authorisations (21) similar to that 2023 (24), illustrating dynamic development therapeutics areas unmet need. The approvals protein (15) advanced therapy medicinal products (ATMPs, 6) indicate a sustained trend also noticeable drugs reviewed this journal last year (16 11, respectively). Clearly, most striking characteristic yield creative pharmacological design, which allows these medicines employ approach target disease. Some notable examples are first successfully using ‘dock‐and‐block’ mechanism inhibition (zenocutuzumab), approved for schizophrenia designed an agonist M 1 /M 4 muscarinic receptors (xanomeline), biparatopic antibody (zanidatamab), binding two distinct epitopes same molecule, haemophilia instead relying on external supplementation clotting factors, restores Factor Xa activity by inhibiting TFPI (marstacimab), or ever direct telomerase inhibitor (imetelstat) reprogrammes oncogenic drive tumour cells. addition, impressive percentage class (28 out 53% total) substantial can be considered disease agnostic, indicating possibility future extensions their use additional indications. demonstrates therapeutic potential innovative effective targeting intractable disorders addresses crucial, needs.

Language: Английский

Citations

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Drug Pipeline for MASLD: What Can Be Learned from the Successful Story of Resmetirom DOI Creative Commons

Elizabeta Knezović,

Marija Hefer,

Suzana Blažanović

et al.

Current Issues in Molecular Biology, Journal Year: 2025, Volume and Issue: 47(3), P. 154 - 154

Published: Feb. 27, 2025

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic steatohepatitis (MASH), represent a growing global health problem linked to obesity, insulin resistance, dyslipidemia. MASLD often leads fibrosis, cirrhosis, hepatocellular carcinoma. Currently, therapeutic options are limited, emphasizing the need for novel, targeted pharmacological interventions. Resmetirom, selective thyroid hormone receptor beta (THR-β) agonist, offers promising approach by specifically enhancing hepatic metabolism while minimizing systemic effects. Clinical trials have demonstrated capacity reduce triglyceride accumulation improve lipid profiles. Early- advanced-phase studies, including MAESTRO program, highlight significant reductions in fat content favorable impacts on noninvasive biomarkers of fibrosis with minimal side This review highlights evidence from pivotal explores resmetirom's mechanism action, compares efficacy safety other emerging agents. While resmetirom marks breakthrough non-cirrhotic MASH management, further long-term studies essential fully evaluate clinical benefits potential regulatory approval broader use MASH.

Language: Английский

Citations

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Prevalence of Metabolic‐Associated Steatotic Liver Disease in Patients With Primary Aldosteronism DOI Creative Commons
Irene Tizianel,

Alberto Madinelli,

Filippo Crimì

et al.

Clinical Endocrinology, Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

ABSTRACT Objective To assess the prevalence of metabolic associated steatotic liver disease (MASLD) in patients with primary aldosteronism (PA) compared to benign adrenal adenomas, and evaluate impact hormonal excess inducing MASLD. Design Single‐centre retrospective study. Methods Hepatic steatosis was assessed by liver/spleen (L/S) ratio from unenhanced abdomen computed tomography images (reference value < 1.1) a cohort 41 PA without cortisol cosecretion, 20 unilateral (uPA) 21 bilateral (BPA), 50 nonfunctioning incidentalomas (NF‐AI), 48 mild autonomous secretion (MACS) 10 Cushing Syndrome (CS). Results increased at diagnosis: L/S lower than NF‐AI (1.1 vs. 1.25, p 0.001) MACS 1.21, 0.007), but similar CS 1.15, = 0.147). A improvement after medical or surgical treatment observed patients, resulting reduced steatosis. MASLD higher (49% 25%, 0.05) 14%, 0.001), 45%, 0.61). uPA had BPA group 71% (53%–89%) versus 25% (7%–43%). Conclusions Prevalence (higher BPA) NFAI, CS.

Language: Английский

Citations

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Resmetirom: the first approved therapy for treating metabolic dysfunction associated steatohepatitis DOI
Sheena Bhushan, Aalam Sohal,

Mazen Noureddin

et al.

Expert Opinion on Pharmacotherapy, Journal Year: 2025, Volume and Issue: unknown

Published: March 18, 2025

Metabolic dysfunction associated steatohepatitis (MASH), previously referred to as nonalcoholic (NASH), has emerged one of the leading indications for liver transplantation in United States. The disease is with increased cardiovascular mortality patients early-stage fibrosis and a heightened risk hepatic complications those advanced fibrosis. Despite its growing prevalence significant healthcare burden, there were no approved drugs treat this chronic disease. In March 2024, Resmetirom, selective thyroid hormone receptor-beta agonist, became first drug receive FDA approval treatment MASH stages F2/F3. This accelerated was granted based on significantly higher rates resolution review summarizes current literature mechanism action, preclinical data, pharmacokinetics, clinical efficacy, indications, contraindications resmetirom management MASH. moderate major advance recent positive results ESSENCE trial semaglutide, if conditional approval, may offer clinicians two options

Language: Английский

Citations

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A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2024 DOI Creative Commons
Zinnet Şevval Aksoyalp, Gizem Kaykı-Mutlu,

Leszek Wojnowski

et al.

Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: March 31, 2025

Abstract The US Food and Drug Administration approved 50 new drugs nine cellular gene therapy products in 2024, i.e., a total of 59 medical therapies. latter group represented three treatments each for oncology hematology/immunotherapy, one neurology, genetic disorders, cardiovascular disorders. Oncology, neurological disorders (14, six, seven, respectively) also were highly prevalent among classic medications. Looking at trends over the past 5 years, we observe greater share first-in-class medications, more fast-track approvals, mRNA/gene/cell-based While small molecules remain largest fraction, their percentage has been declining substantially years. Taking together, these findings testify to commitment pharmaceutical industry innovative treatments, including conditions which no therapies existed. On other hand, there is trend approvals narrowly focused such as tumors defined by alterations.

Language: Английский

Citations

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Evaluation of the hepatic and subcutaneous adipose tissue effects of triiodothyronine treatment in an animal model of metabolic syndrome DOI
Marta Borges‐Canha, Ana Rita Leite, Glória Conceição

et al.

Obesity Research & Clinical Practice, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

0
Clinical Insights on Resmetirom DOI
Eda Kaya, Yusuf Yılmaz,

Naim Alkhouri

et al.

Journal of Clinical Gastroenterology, Journal Year: 2025, Volume and Issue: 59(5), P. 412 - 419

Published: Feb. 13, 2025

The recent conditional approval by the Food and Drug Administration of resmetirom for treating metabolic dysfunction-associated steatohepatitis (MASH) with significant or advanced fibrosis represents a pivotal milestone in history steatotic liver disease (MASLD) treatment. As first liver-directed pharmacological therapy option MASLD, offers novel approach that specifically targets pathology, marking transformative step forward managing this widespread challenging condition. For initiating resmetirom, biopsy is not required. Consequently, accurately excluding patients less severe histology cirrhosis using noninvasive tests (NITs) essential. In addition, monitoring response should be conducted NITs. Given approval, our current clinical understanding primarily informed phase 3 trials. long-term effects drug evaluated further studies encouraging use eligible patients. This review highlights key aspects use, including identifying target population, therapeutic response, determining appropriate discontinuation criteria, strategies to prevent unnecessary treatment interruptions.

Language: Английский

Citations

0