Pettinato Mariateresa, Furiosi Valeria, Carleo Rossana, Bavuso Volpe Letizia, Guo Shuling, Mannella Valeria, Musco Giovanna, Gilberti Enrica, De Palma Giuseppe, Federico Giorgia, Carlomagno Francesca, Cherubini Alessandro, Pelusi Serena, Dano Anxhela, Nai Antonella, Valenti Luca, Altamura Sandro, Pagani Alessia, Silvestri Laura
Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy.
Università Vita-Salute San Raffaele, Milan, Italy.
Liver Int. 2025 Jul;45(7):e70163. doi: 10.1111/liv.70163.
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.
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.
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.
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.
代谢功能障碍相关脂肪性肝病（MASLD）是肝病最常见的病因，也是肝脏相关发病率和死亡率的主要促成因素。目前，尚无药物治疗方法对所有患者均显示出持续且长期的疗效。因此，确定新的治疗靶点仍是一项紧迫的临床需求。由TMPRSS6编码的肝脏丝氨酸蛋白酶matriptase-2可抑制BMP-SMAD通路。有趣的是，肝脏中BMP-SMAD信号传导减弱常与患者脂质代谢改变相关。相反，Tmprss6失活与高脂饮食诱导的肥胖减轻有关。基于这些发现，我们推测TMPRSS6是治疗MASLD的一个新的有前景的靶点。
分析了有或无MASLD的肥胖患者肝脏中TMPRSS6的表达。成年雄性小鼠喂食MASLD-MASH饮食，一旦肝脂肪变性形成，在继续饮食方案额外6周的同时，用靶向Tmprss6的反义寡核苷酸进行治疗。
MASLD患者中BMP-SMAD抑制剂TMPRSS6的表达增加，且与肝脏脂质代谢的关键调节因子PPARα信号呈负相关。在实验性MASLD中，使用GalNAc-ASO下调肝细胞Tmprss6可显著减轻脂肪性肝炎和肝纤维化，并通过重塑肝脏转录因子活性，使其向PPARα和SMAD4/SMAD5驱动的信号传导方向转变，从而减轻MASLD-MASH相关的铁死亡。同样，增强的BMP-SMAD信号在体内增加了PPARα活性。
我们的研究结果揭示了TMPRSS6与PPARα之间一种新的功能相互作用。实验性MASLD中Tmprss6的药理学下调通过增强PPARα信号传导和减轻铁死亡，减轻了肝脂肪变性、炎症和纤维化。
