ArticleLiver international : official journal of the International Association for the Study of the Liver2025
Targeting the Liver Serine Protease TMPRSS6 Ameliorates Steatosis and Attenuates Fibrosis in Experimental MASLD.
Article in Liver international : official journal of the International Association for the Study of the Liver, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 2 papers.
What it found
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Who cites it
2 citing papers in PubMed.
- Therapeutic Silencing of Tmprss6 Reduces Iron-Induced Inflammation and Prolongs Survival in MDS Mice.American journal of hematology · 2026Article
- Asialoglycoprotein receptor 1: a multifaceted receptor in the liver and cardiovascular system.Frontiers in medicine · 2025Review
Corrections and comments
- Erratum issued
Authors and funding
19 authors.
Funding
Abstract
BACKGROUND AND
aimsMetabolic 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.
methodsHepatic 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.
resultsThe 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.
conclusionsOur 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.
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