Estrogen-dependent TRX2 activation reverts oxidative stress and metabolic dysfunction associated to steatotic disease

Abstract Metabolic disfunction-associated steatotic liver disease (MASLD) encompasses a plethora of hepatic disorders ranging from steatosis to steatohepatitis with the worst clinical outcome represented by cirrhosis, liver failure, and hepatocellular carcinoma. According to the lower MASLD prevalence reported in pre-menopausal women compared to men, we identified a potential protective role of estrogens in counteracting the oxidative stress during disease induction and progression. We have used preclinical relevant in vitro models [i.e., immortalized cells and hepatocyte-like cells (HLC) derived from human embryonic stem cells (hESC)], exposed to sodium lactate, sodium pyruvate, and octanoic acid (LPO) to induce hepatic steatosis. This established practice of MASLD induction resulted in lipid droplet (LD) accumulation and increased mitochondrial and cytosolic reactive oxygen species (ROS) levels, paralleled by the reduction of several markers of hepatocyte function and differentiation. Here we found that estrogen replacement reduced ROS levels and LD content through the upregulation of mitochondrial thioredoxin 2 (TRX2), an antioxidant system that is under the control of the estrogen receptor alpha (hereafter referred as ER). Last, disrupting the TRX2 system using auranofin was sufficient to revert the scavenging effects exerted by estrogens, thus identifying a potential mechanism that could prevent or delay the progression of the disease.