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

Metabolic-Dysfunction-Associated Steatotic Liver Disease: Molecular Mechanisms, Clinical Implications, and Emerging Therapeutic Strategies DOI Open Access

Jeysson E. Mejía-Guzmán,

Ramón A. Belmont-Hernández,

Norberto C. Chávez‐Tapia

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 2959 - 2959

Published: March 25, 2025

Metabolic-dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty (NAFLD), is a highly prevalent metabolic disorder characterized by hepatic steatosis in conjunction with at least one cardiometabolic risk factor, such obesity, type 2 diabetes, hypertension, or dyslipidemia. As global rates of obesity and syndrome continue to rise, MASLD becoming major public health concern, projections indicating substantial increase prevalence over the coming decades. The spectrum ranges from simple metabolic-dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, hepatocellular carcinoma, contributing significant morbidity mortality worldwide. This review delves into molecular mechanisms driving pathogenesis, including dysregulation lipid metabolism, chronic inflammation, oxidative stress, mitochondrial dysfunction, gut microbiota alterations. Recent advances research have highlighted role genetic epigenetic factors progression, well novel therapeutic targets peroxisome proliferator-activated receptors (PPARs), fibroblast growth factors, thyroid hormone receptor beta agonists. Given multifaceted nature MASLD, multidisciplinary approach integrating early diagnosis, insights, lifestyle interventions, personalized therapies critical. underscores urgent need for continued innovative treatment strategies precision medicine approaches halt progression improve patient outcomes.

Language: Английский

Citations

1
FDA’s approval of resmetirom (Rezdiffra): a breakthrough in MASH management DOI Creative Commons

Muhammad Mazhar Azam,

Sameen Mukhtar,

Muhammad Haris

et al.

Published: Dec. 3, 2024

The FDA’s approval of resmetirom (Rezdiffra) marks a significant breakthrough in treating metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis, conditions linked to non-alcoholic fatty liver disease (NAFLD). MASH is growing global health concern, offers novel therapeutic option by targeting pathophysiology through thyroid hormone receptor-beta activation. This mechanism effectively reduces fibrosis markers, improves enzyme levels, minimizes fat buildup. Clinical trials have shown that has favorable safety profile, with manageable side effects like diarrhea nausea. Additionally, it may lower cardiovascular risks associated MASH, enhancing patient outcomes quality life. As the first FDA-approved drug for resmetirom’s introduction fills crucial treatment gap, providing new hope millions patients representing pivotal moment hepatology.

Language: Английский

Citations

3
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
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

Citations

2