2025-06-112025-06-112024-03-23González Recio, I., Goikoetxea Usandizaga, N., Rejano Gordillo, C.M., Conter, C., Rodríguez Agudo, R., Serrano Maciá, M.,...,Martínez Chantar, M.L. (2024). Modulatory effects of CNNM4 on protein-L-isoaspartylO-methyltransferase repair function during alcohol-induced hepatic damage. Hepatology, 10.1097/HEP.0000000000001156. https://doi.org/10.1097/HEP.0000000000001156.1527-33500270-9139https://hdl.handle.net/11441/174220Background and Aims: Alcohol-associated liver disease (ALD) is a,leading cause of liver-related mortality worldwide, with limited treatment,options beyond abstinence and liver transplantation. Chronic alcohol,consumption has been linked to magnesium (Mg2+) deficiency, which can,influence liver disease progression. The mechanisms underlying Mg2+,homeostasis dysregulation in ALD remain elusive. This study aimed to,investigate the role of the Mg2+ transporter Cyclin M4 (CNNM4) in ALD by,analyzing its expression patterns in patients with ALD and preclinical,animal models.,Approach and Results: In this study, CNNM4 is upregulated in the liver of,both patients with ALD and animal models. CNNM4 overexpression triggers Mg2+ homeostasis dysregulation, linked to ALD progression. We,propose a novel therapeutic approach for ALD treatment using N-acetylgalactosamine silencing RNA technology to specifically modulate,Cnnm4 expression in the liver, improving mitochondrial function and alleviating endoplasmic reticulum stress. Notably, silencing Cnnm4 restores,protein isoaspartyl methyltransferase (PCMT1) activity, essential for,repairing ethanol-induced protein damage. Enhancing mitochondrial,activity through Cnnm4-dependent mechanisms increases S-adenosylmethionine levels, crucial for PCMT1 function, highlighting the interconnected roles of mitochondrial health and protein homeostasis in ALD,treatment.,Conclusions: These findings shed light on the dysregulation of Mg2+,homeostasis in ALD, providing a promising therapeutic approach targeting,CNNM4. N-acetylgalactosamine siCnnm4 therapy boosts the repair processes of ethanol-damaged proteins through the upregulation of PCMT1,activity.application/pdf18 p.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/AlcoholALDHepatotoxicityMagnesiuminfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccesshttps://doi.org/10.1097/HEP.0000000000001156