Targeting magnesium homeostasis: a novel therapeutic strategy for liver diseases

This review systematically examines a novel therapeutic strategy for liver disease prevention and treatment by targeting magnesium ion homeostasis. Magnesium ions (Mg²⁺), an essential macromineral, plays a critical role in energy metabolism and enzymatic activity, with its systemic balance maintained through intestinal absorption, renal excretion, and skeletal storage. Emerging evidence demonstrates that hypomagnesemia or intracellular magnesium deficiency is strongly associated with the development and progression of various liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcoholic liver disease (ALD), drug-induced liver injury (DILI), and hepatocellular carcinoma (HCC). Mechanistically, magnesium deficiency exacerbates hepatic pathology by promoting insulin resistance, impairing mitochondrial function, inducing oxidative stress and inflammatory responses, disrupting gut-liver axis homeostasis, and compromising DNA repair and anti-tumor immunity. Preclinical and preliminary clinical studies indicate that restoring magnesium homeostasis-through dietary supplementation, magnesium-based pharmacological agents, or modulation of magnesium transporters [e.g., inhibition of the Mg²⁺ efflux transporter Cyclin M4 (CNNM4)]-can improve metabolic function in hepatocytes, attenuate inflammation and fibrosis, and exert hepatoprotective effects. Collectively, these findings highlight magnesium homeostasis as a promising therapeutic target for liver disease, warranting further validation in large-scale clinical trials to facilitate clinical translation.