Copper and hepatic lipid dysregulation: Mechanisms and implications

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) and Wilson's disease (WD) are common clinical conditions characterized by hepatic steatosis. Copper has been associated with the progression of hepatic steatosis, but its precise mechanism remains unclear. Emerging research on hepatic copper homeostasis- including its role in liver aging, cuproptosis induction, and lipid metabolism dysregulation-highlighted its significance in liver pathophysiology. Multiple mechanisms have been implicated in copper-induced hepatic lipid metabolism abnormalities, including oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, impaired glucose metabolism, AMPK activation, hepatic nuclear receptor modulation, and cuproptosis. Both copper excess and deficiency could trigger hepatic steatosis via these pathways. This review systematically summarized intracellular copper metabolism regulation, elucidated potential mechanisms of copper-induced hepatic lipid dysregulation, and analyzed copper-lipid metabolism interactions in MASLD and WD. These findings provide insights into the mechanisms by which copper contributes to hepatic steatosis and offer a theoretical basis for targeting copper homeostasis as a therapeutic strategy in the treatment of liver diseases.