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Targeting the liver serine protease TMPRSS6 ameliorates steatosis and attenuates fibrosis in experimental MASLD

Background and Aims Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of liver disease and a leading contributor to liver-related morbidity and mortality. Currently, no pharmacological approach has demonstrated consistent and long-lasting benefits across all p...

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Main Authors: Pettinato, Mariateresa (Author) , Furiosi, Valeria (Author) , Carleo, Rossana (Author) , Bavuso Volpe, Letizia (Author) , Guo, Shuling (Author) , Mannella, Valeria (Author) , Musco, Giovanna (Author) , Gilberti, Enrica (Author) , De Palma, Giuseppe (Author) , Federico, Giorgia (Author) , Carlomagno, Francesca (Author) , Cherubini, Alessandro (Author) , Pelusi, Serena (Author) , Dano, Anxhela (Author) , Nai, Antonella (Author) , Valenti, Luca (Author) , Altamura, Sandro (Author) , Pagani, Alessia (Author) , Silvestri, Laura (Author)
Format: Article (Journal)
Language:English
Published: July 2025
In: Liver international
Year: 2025, Volume: 45, Issue: 7, Pages: 1-17
ISSN:1478-3231
DOI:10.1111/liv.70163
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1111/liv.70163
Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1111/liv.70163
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Author Notes:Mariateresa Pettinato, Valeria Furiosi, Rossana Carleo, Letizia Bavuso Volpe, Shuling Guo, Valeria Mannella, Giovanna Musco, Enrica Gilberti, Giuseppe De Palma, Giorgia Federico, Francesca Carlomagno, Alessandro Cherubini, Serena Pelusi, Anxhela Dano, Antonella Nai, Luca Valenti, Sandro Altamura, Alessia Pagani, Laura Silvestri
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Summary:Background and Aims Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of liver disease and a leading contributor to liver-related morbidity and mortality. Currently, no pharmacological approach has demonstrated consistent and long-lasting benefits across all patients. Therefore, identifying new therapeutic targets remains an urgent clinical need. The hepatic serine protease matriptase-2, encoded by TMPRSS6, inhibits the BMP-SMAD pathway. Interestingly, reduced BMP-SMAD signalling in the liver is frequently associated with altered lipid metabolism in patients. Conversely, inactivation of Tmprss6 has been linked to reduced high-fat diet-induced obesity. Based on these findings, we hypothesize that TMPRSS6 represents a novel and promising target for the treatment of MASLD. Methods Hepatic TMPRSS6 expression was analysed in obese patients with or without MASLD. Adult male mice were fed a MASLD-MASH diet, and once hepatosteatosis was established, they were treated with antisense oligonucleotides targeting Tmprss6 while continuing the dietary regimen for an additional 6 weeks. Results The expression of the BMP-SMAD inhibitor TMPRSS6 was increased in people with MASLD and negatively correlated with PPARα signaling, a key regulator of hepatic lipid metabolism. In experimental MASLD, downregulation of hepatocytic Tmprss6 using GalNAc-ASO significantly reduced steatohepatitis and fibrosis and attenuated MASLD-MASH-associated ferroptosis by reshaping hepatic transcription factor activity towards PPARα and SMAD4/SMAD5-driven signalling. Consistently, enhanced BMP-SMAD signalling increased PPARα activity in vivo. Conclusions Our findings reveal a novel functional crosstalk between TMPRSS6 and PPARα. Pharmacological downregulation of Tmprss6 in experimental MASLD mitigates hepatosteatosis, inflammation and fibrosis by enhancing PPARα signalling and attenuating ferroptosis.
Item Description:Zuerst veröffentlicht: 11. Juni 2025
Gesehen am 06.11.2025
Physical Description:Online Resource
ISSN:1478-3231
DOI:10.1111/liv.70163

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