Statin-Induced Geranylgeranyl Pyrophosphate Depletion Promotes Ferroptosis-Related Senescence in Adipose Tissue

Abstract

Statin treatment is accepted to prevent adverse cardiovascular events. However, atorvastatin, an HMG-CoA reductase inhibitor, has been reported to exhibit distinct effects on senescent phenotypes. Whether atorvastatin can induce adipose tissue senescence and the mechanisms involved are unknown. The effects of atorvastatin-induced senescence were examined in mouse adipose tissue explants. Here, we showed that statin initiated higher levels of mRNA related to cellular senescence markers and senescence-associated secretory phenotype (SASP), as well as increased accumulation of the senescence-associated β-galactosidase (SA-β-gal) stain in adipose tissues. Furthermore, we found that the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and Fe2+ were elevated in adipose tissues treated with atorvastatin, accompanied by a decrease in the expression of glutathione (GSH), and glutathione peroxidase 4 (GPX4), indicating an iron-dependent ferroptosis. Atorvastatin-induced was prevented by a selective ferroptosis inhibitor (Fer-1). Moreover, supplementation with geranylgeranyl pyrophosphate (GGPP), a metabolic intermediate, reversed atorvastatin-induced senescence, SASP, and lipid peroxidation in adipose tissue explants. Atorvastatin depleted GGPP production, but not Fer-1. Atorvastatin was able to induce ferroptosis in adipose tissue, which was due to increased ROS and an increase in cellular senescence. Moreover, this effect could be reversed by the supplement of GGPP. Taken together, our results suggest that the induction of ferroptosis contributed to statin-induced cell senescence in adipose tissue.

Iron: The silent culprit in your adipose tissue

“…Emerging research suggests that increased markers of ferroptosis in adipose tissue may contribute to a phenotype of adipose tissue dysfunction characterized by heightened inflammation and cellular senescence. This effect can result in the attenuation of the ability to store lipids in white adipose tissue and reduced thermogenic activity in brown adipose tissue 69–72 . However, it is essential to conduct further studies to fully understand the significance of ferroptosis in adipose tissue physiology.…”

“…This effect can result in the attenuation of the ability to store lipids in white adipose tissue and reduced thermogenic activity in brown adipose tissue. [69][70][71][72] However, it is essential to conduct further studies to fully understand the significance of ferroptosis in adipose tissue physiology.…”

Ferroptosis: a new hunter of hepatocellular carcinoma

“…The suppression of the HMG-CoA reductase by statins leads to decreased expression of glutathione peroxidase 4 (GPX4), a key regulator of lipid peroxidation, which in turn results in lipid ROS production and induction of ferroptosis. Experimental data suggest that statins may act as anti-cancer drugs by enhancing tumor cells’ ferroptosis [ 173 , 174 ].…”

The Link between Magnesium Supplements and Statin Medication in Dyslipidemic Patients

“…The following effectors (Rho kinase, nicotinamide adenine dinucleotide phosphate oxidases) will be also inhibited. The final result is a decreased proliferation of myocardial fibroblasts and inhibition of collagen proliferation [ 59 , 64 , 65 ].…”