Biology subjects

Thewes, L.

Publications and source records attributed to Thewes, L..

3 recordsLinked to original sources

bioRxiv2025

Redox homeostasis in ferroptosis and aging: a causal role for fard-1 and dhs-25 in Caenorhabditis elegans

Aging is a natural process characterized by a progressive physiological decline that undermines health and well-being in the elderly population. It is widely accepted that an unbalanced redox state belongs to the hallmarks of aging, but its role as one of the main drivers of ferroptosis is quite recent. Ferroptosis is a form of iron-dependent cell death caused by massive phospholipid peroxidation. The excessive accumulation of intracellular reactive oxygen species and iron, as well as the failure of the main cellular antioxidant systems, cause ferroptotic cell death. While clear roles for ferroptosis in pathological conditions such as cancer or neurodegeneration have been described, its physiological roles and regulators are less clearly understood. Here, using Caenorhabditis elegans as a powerful model organism for aging studies, we uncover a role for ferroptosis in physiological aging mediated by disturbed redox homeostasis. We evaluated healthspan parameters in a C. elegans wild-type strain highlighting how several age-related features differentially decline during aging. A progressive loss of the capability to contrast external stressors, with an increase in hydroxyl radicals and a failure of the glutathione antioxidant system demonstrated the progressive disruption of redox homeostasis in older age. Moreover, we showed that selected genes involved in redox metabolism are downregulated with aging. Among them, mutant strains of the fatty acyl-CoA reductase, fard-1, and of the dehydrogenase, dhs-25, displayed higher sensitivity to a ferroptosis inducer, increased lipid peroxidation, anticipated drop in total glutathione and reduced lifespan. Accordingly, the expression of one of the closest mammalians dhs-25 homolog, the hydroxysteroid 17-Beta Dehydrogenase 8, was downregulated in cells which are more sensitive to ferroptosis. Our results clearly prove a causal role for ferroptosis in C. elegans aging driven by oxidative stress, unveiling novel genes involved in this connection that may constitute targets for possible interventions to improve healthy aging.

cell biology↗

bioRxiv2024

Oncogenic RAS signaling suppresses ferroptosis via transcriptional upregulation of GCH1

Ferroptosis is an iron-dependent form of regulated cell death arising from excessive lipid peroxidation. The role of oncogenic RAS signaling in modulating the cellular response to ferroptosis is controversial. While seminal studies described that oncogenic RAS transformation drives a synthetic lethal vulnerability to archetypal ferroptosis inducers including erastin (eradicator of RAS and ST-expressing cells) and RSL3 (Ras selective lethal 3), more recent work suggest that oncogenic RAS signaling may confer ferroptosis resistance. Thus, the impact of oncogenic RAS expression on ferroptosis sensitivity is still poorly understood. Here, using orthogonal cellular systems across multiple classes of ferroptosis- inducing agents, as well as in silico therapeutic drug-response analyses, we provide unifying evidence that oncogenic RAS signaling suppresses ferroptosis. Integrated proteo- and transcriptomic analyses in oncogenic RAS-transformed cells further uncovered that RAS signaling upregulates the ferroptosis suppressor GTP cyclohydrolase I (GCH1) via transcriptional induction by the transcription factor ETS1 downstream of the RAS-MAPK signaling cascade. Targeted repression of Gch1 or of Gch1-controlled tetrahydrobiopterin (BH4) synthesis pathway is sufficient to sensitize RAS-mutant cell lines to ferroptosis in 2D and 3D cell models, as well as in tumor organoids and tumor xenografts, highlighting a mechanism through which RAS promotes resistance to ferroptosis induction. Furthermore, we found that GCH1 expression is clinically relevant and correlates with RAS signaling activation in human cancers. Overall, this study redefines oncogenic RAS signaling to be a ferroptosis suppressor, and identifies GCH1 as a mediator of this effect and a potential clinical target for the sensitization of RAS-driven cancers to ferroptosis-inducing agents. Significance StatementAlthough it is commonly accepted that ferroptosis induction is a mutant RAS-selective lethality, accumulating evidence suggests that oncogenic RAS protects cells against this form of cell death. However, a systematic survey establishing the relationship between RAS and ferroptosis sensitivity is lacking, and the molecular mechanisms this entails are still poorly understood. Here, we report across RAS-mutant isoforms, in diverse cellular models, and using multiple ferroptosis-inducing compounds that oncogenic RAS consistently suppresses ferroptosis. Further, we show that oncogenic RAS-mediated ferroptosis suppression is attributed to the upregulation of GCH1 and its downstream metabolite, tetrahydrobiopterin. Our study delivers a shift towards a new paradigm in which oncogenic RAS confers ferroptosis resistance, and a potential clinical strategy to re-engage ferroptosis sensitivity in RAS-driven cancers.

cancer biology↗

bioRxiv2022

JNK signalling regulates self-renewal of proliferative urine-derived renal progenitor cells via inhibition of ferroptosis

With a global increase in chronic kidney disease patients, alternatives to dialysis and organ transplantation are needed. Stem cell-based therapies could be one possibility to treat chronic kidney disease. Here, we used multipotent urine-derived renal progenitor cells (UdRPCs) to study nephrogenesis. UdRPCs treated with the JNK inhibitor-AEG3482, displayed decreased proliferation and downregulated transcription of cell cycle-associated genes as well as the kidney progenitor markers -SIX2, CITED1, and SALL1. In addition, levels of activated SMAD2/3, which is associated with the maintenance of self-renewal in UdRPCs, were decreased. JNK inhibition resulted in less efficient oxidative phosphorylation and more lipid peroxidation via ferroptosis-an iron-dependent non-apoptotic cell death pathway linked to various forms of kidney disease. Our study reveals the importance of JNK signalling in maintaining self-renewal as well as protection against ferroptosis in SIX2-positive UdRPCs. We propose that UdRPCs can be used for modelling ferroptosis-induced kidney diseases.

cell biology↗