Uncovering the Metabolic and Stress Responses of Human Embryonic Stem Cells to FTH1 Gene Silencing

Abstract

Embryonic stem cells (ESCs) are pluripotent cells with indefinite self-renewal ability and differentiation properties. To function properly and maintain genomic stability, ESCs need to be endowed with an efficient repair system as well as effective redox homeostasis. In this study, we investigated different aspects involved in ESCs’ response to iron accumulation following stable knockdown of the ferritin heavy chain (FTH1) gene, which encodes for a major iron storage protein with ferroxidase activity. Experimental findings highlight unexpected and, to a certain extent, paradoxical results. If on one hand FTH1 silencing does not correlate with increased ROS production nor with changes in the redox status, strengthening the concept that hESCs are extremely resistant and, to a certain extent, even refractory to intracellular iron imbalance, on the other, the differentiation potential of hESCs seems to be affected and apoptosis is observed. Interestingly, we found that FTH1 silencing is accompanied by a significant activation of the nuclear factor (erythroid-derived-2)-like 2 (Nrf2) signaling pathway and pentose phosphate pathway (PPP), which crosstalk in driving hESCs antioxidant cascade events. These findings shed new light on how hESCs perform under oxidative stress, dissecting the molecular mechanisms through which Nrf2, in combination with PPP, counteracts oxidative injury triggered by FTH1 knockdown.

NRF2 and the Moirai: Life and Death Decisions on Cell Fates

“…Another study demonstrated that mild oxidative stress provoked by exposure to glucose oxidase enhanced osteogenic differentiation and mineralization in mouse ESCs, which was inhibited by Nrf2 knockdown (Sim et al, 2016 ). It was reported that silencing of FTH1 , which encodes a major iron storage protein, activated NRF2 signaling and induced expression of metabolism-related NRF2 target genes, G6PD and PGD in hESCs (Scaramuzzino et al, 2021 ). Considering NRF2 as a transcription factor that modulates Fth1 and also ferritin light chain ( Ftl ) transcription (Kwak et al, 2001 ; Thimmulappa et al, 2002 ), it could be assumed that the FTH1 -NRF2 axis might contribute to iron homeostasis in hESCs, leading to metabolic changes.…”

Herpes Simplex Virus 1-Induced Ferroptosis Contributes to Viral Encephalitis

“…To further explore the details of HSV-1-induced ferroptosis, we focused on the antioxidative genes implicated in negatively regulating ferroptosis, including ferritin heavy chain 1 (FTH1), cystine/glutamate antiporter xCT (SLC7A11), the glutamate-cysteine ligase catalytic subunit (GCLC), the glutamate-cysteine ligase modifier (GCLM), and GPX4. FTH1 is a major component of ferritin, an iron storage protein complex that prevents the iron-mediated production of ROS ( 27 ). SLC7A11 is a key component of the Xc system that ingests extracellular cystine in cells, which is then reduced to cysteine for GSH biosynthesis ( 28 ).…”

Ginsenoside Rh4 Inhibits Colorectal Cancer Cell Proliferation by Inducing Ferroptosis via Autophagy Activation

“…During autophagy, p62 is degraded, leading to the downregulation of NRF2 expression and decreased antioxidant levels in cells [ 66 ]. The decrease in cellular antioxidant levels leads to increased NCOA4 expression levels, which promote the degradation of FTH1 and the expression of DMT1 [ 67 , 68 ]. The degradation of FTH1 leads to iron release, while DMT1 increases iron absorption, leading to iron overload in cells [ 69 , 70 ].…”