Ferroptosis resistance cooperates with cellular senescence in the overt stage of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Abstract

Cellular senescence and ferroptosis are the two main, fine-tuned processes in tissue damage restraint; however, they can be overactivated in pathologies such as nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH), becoming dangerous stimuli. Senescence is characterized by a decline in cell division and an abnormal release of reactive oxygen species (ROS), and ferroptosis is represented by iron deposition associated with an excessive accumulation of ROS. ROS and cellular stress pathways are also drivers of NAFLD/NASH development. The etiology of NAFLD/NASH lies in poor diets enriched in fat and sugar. This food regimen leads to liver steatosis, resulting in progressive degeneration of the organ, with a late onset of irreversible fibrosis and cirrhosis. Few studies have investigated the possible connection between senescence and ferroptosis in NAFLD/NASH progression, despite the two events sharing some molecular players. We hypothesized a possible link between senescence and ferroptosis in a NAFLD background. To thoroughly investigate this in the context of “Western-style” diet (WSD) abuse, we used an amylin-modified liver NASH mouse model. The main NASH hallmarks have been confirmed in this model, as well as an increase in apoptosis, and Ki67 and p53 expression in the liver. Senescent beta-galactosidase-positive cells were elevated, as well as the expression of the related secretory molecules Il-6 and MMP-1. Features of DNA damage and iron-overload were found in the livers of NASH mice. Gpx4 (glutathione peroxidase 4) expression, counteracting ferroptotic cell death, was increased. Notably, an increased number of senescent cells showing overexpression of gpx4 was also found. Our data seem to suggest that senescent cells acquire a gpx4-mediated mechanism of ferroptosis resistance and thus remain in the liver, fostering the deterioration of liver fitness.

Melatonin Repairs Osteoporotic Bone Defects in Iron-Overloaded Rats through PI3K/AKT/GSK-3β/P70S6k Signaling Pathway

“…Ghasemi et al discovered that iron overload decreases the activity of antioxidant enzymes in the liver, causing the liver to create a significant concentration of ROS and impairing liver function [ 36 ]. Vetuschi et al showed that iron overload could antagonize ferroptosis through negative feedback regulation of hepatic release of glutathione peroxidase 4 [ 37 ]. Through its potential to eliminate free radicals, melatonin exhibits its antioxidant actions and protects the liver from oxidative stress [ 38 ].…”

Polystyrene Nano- and Microplastic Particles Induce an Inflammatory Gene Expression Profile in Rat Neural Stem Cell-Derived Astrocytes In Vitro

“…Increased HMGB1 is considered the hallmark of senescent astrocytes [ 69 ] and the HMGB1 signaling canonical pathway was activated by both PS particles. The SASP secretome, which results from excessive senescence, alerts the immune system to the onset of injury, coordinates the deletion of senescent cells and can contribute to increased cancer risk and age-related diseases [ 110 , 111 , 112 , 113 ]. Studies have shown that exposure to MPs/NPs leads to increased cellular senescence, as seen in rat lung tissue, zebrafish gills, and porcine coronary artery endothelial cells exposed to PS-MPs [ 114 , 115 , 116 ].…”

Astragaloside IV attenuates myocardial dysfunction in diabetic cardiomyopathy rats through downregulation of CD36‐mediated ferroptosis

“…PAs, as representative long‐chain non‐esterified SFAs, confer strong lipotoxic effects and can trigger several types of cell death. An in vitro experimental study has shown that PAs can induce ferroptosis and lipid deposition through the regulation of ferroptosis‐related factors (Vetuschi et al, 2022).…”

“…*P < 0.05, **P < 0.01 as compared with BSA; # P < 0.05, ## P < 0.01 as compared with PA; + P < 0.05, ++ P < 0.01 as compared with PA + AS IV 80. converted to triglycerides, which then accumulate in cardiomyocytes and subsequently damage them, eventually leading to cell death (Hu et al, 2021). PAs are the most abundant saturated fatty acid (SFA) in the body, accounting for 25%-32% of the total serum FAs (Chu et al, 2019) through the regulation of ferroptosis-related factors (Vetuschi et al, 2022).…”