Biology subjects

Friedmann Angeli, J. P.

Publications and source records attributed to Friedmann Angeli, J. P..

6 recordsLinked to original sources

bioRxiv2026

Artesunate Exploits Glutathione-Dependent Redox Vulnerability in Metastatic Lung Adenocarcinoma

Metastatic dissemination remains the principal cause of mortality in lung adenocarcinoma. To identify metabolic vulnerabilities associated with metastasis, we used cell lines with distinct metastatic abilities derived from the KrasG12D;p53KO mouse model. Building on evidence of mitochondrial dysfunction in metastasis-derived cells, we performed an in vivo screen of a focused metabolic drug library using a multiplexed DNA-barcoding platform. This approach identified artesunate as a selective inhibitor of metastatic seeding, which was validated in vivo to reduce metastatic burden while leaving primary tumor growth unaffected. Mechanistically, artesunate induced oxidative stress, characterized by reactive oxygen species and lipid peroxidation. Transcriptomic and mechanistic profiling revealed altered redox homeostasis in metastasis-derived cells. Inhibition of glutathione synthesis specifically sensitized these cells to artesunate, resulting in extensive cell death, whereas primary tumor-derived cells remained resistant. These findings identify glutathione-dependent redox homeostasis as a metabolic vulnerability in metastatic cells that can be specifically targeted using artesunate.

cancer biology↗

bioRxiv2026

Oxysterol-sensing by Liver X receptor counteracts ferroptosis via lipid remodeling

Ferroptosis, an iron-dependent form of regulated cell death, is controlled by cellular metabolism. Nutrients and metabolites determine cell states that render cells sensitive or resistant to ferroptosis. Nuclear receptors can act as cellular sensors for distinct metabolites and nutrients to regulate ferroptosis. We performed a chemical genetics screen using a nuclear receptor small molecule library to identify novel regulators of ferroptosis. We find that activating or overexpressing the liver X receptor (LXR) suppresses ferroptosis in various cell models, including ex vivo primary mouse hepatocytes. Interestingly, hepatocellular carcinoma with high levels of LXR shows poorer survival outcomes. In cells, activation of LXR by the endogenous oxysterol 24(S),25-epoxycholesterol or synthetic agonists reduces lipid peroxidation and ferroptotic cell death. Mechanistically, LXR activation drives a selective transcriptional program upregulating SREBP-1c, SCD1 and ACSL3, key enzymes involved in the synthesis of monounsaturated fatty acid-containing phospholipids (MUFA-PLs). Lipidomic analysis reveals that this lipid remodeling enriches cellular membranes with MUFA-PLs, reducing their susceptibility to peroxidation and thereby counteracting ferroptosis. Together, we identify LXR as an oxysterol-sensing endogenous suppressor of ferroptosis coupling oxysterol sensing to the adaptive remodeling of cellular membrane lipid composition to limit lipid peroxidation.

cell biology↗

bioRxiv2025

Riboflavin metabolism shapes FSP1-driven ferroptosis resistance

Membrane protection against oxidative insults is achieved by the concerted action of glutathione peroxidase 4 (GPX4) and endogenous lipophilic antioxidants such as ubiquinone and vitamin E. Deficiencies in these protective systems lead to an increased propensity to phospholipid peroxidation and ferroptosis. More recently, ferroptosis suppressor protein 1 (FSP1) was identified as a critical ferroptosis inhibitor acting via regeneration of membrane-embedded antioxidants. Yet, regulators of FSP1 are largely uncharacterised, and their identification is essential for understanding the mechanisms buffering phospholipid peroxidation and ferroptosis. Here, we conducted a focused CRISPR-Cas9 screen to uncover factors influencing FSP1 function, identifying riboflavin (vitamin B2) as a new modulator of ferroptosis sensitivity. We demonstrate that riboflavin, unlike other vitamins that act as radical-trapping antioxidants, supports FSP1 stability and the recycling of lipid-soluble antioxidants, thereby mitigating phospholipid peroxidation. Furthermore, we show that the riboflavin antimetabolite roseoflavin markedly impairs FSP1 function and sensitises cancer cells to ferroptosis. Thus, we uncover a direct and actionable role for riboflavin in maintaining membrane integrity by promoting membrane tolerance to lipid peroxidation. Our findings provide a rational strategy to modulate the FSP1-antioxidant recycling pathway and underscore the therapeutic potential of targeting riboflavin metabolism, with implications for understanding the interaction of nutrients and their contributions to a cells antioxidant capacity.

cell biology↗

bioRxiv2024

PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance

Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and has traditionally been thought to begin with the uptake of the Sec carrier selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP undergoes metabolisation via selenocysteine lyase (SCLY), producing selenide, a substrate used by selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor - selenophosphate - for the biosynthesis of the selenocysteine tRNA. Here, we report the discovery of an alternative pathway mediating Sec metabolisation that is independent of SCLY and mediated by peroxiredoxin 6 (PRDX6). Mechanistically, we demonstrate that PRDX6 can readily react with selenide and interact with SEPHS2, potentially acting as a selenium delivery system. Moreover, we demonstrate the presence and functional significance of this alternative route in cancer cells where we reveal a notable association between elevated expression of PRDX6 with a highly aggressive neuroblastoma subtype. Altogether, our study sheds light on a previously unrecognized aspect of Sec metabolism and its implications in ferroptosis, offering new avenues for therapeutic exploitation.

cell biology↗

bioRxiv2022

Selenocysteine metabolism is a targetable vulnerability in MYCN-amplified cancers

Understanding the operational molecular, and metabolic networks that determine the balance between pro- and anti-ferroptotic regulatory pathways could unravel unique vulnerabilities to be exploited for cancer therapy. Here we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis in vitro and in orthotopic neuroblastoma mouse models. Specifically, the exquisite dependency on LRP8-mediated selenocysteine import is caused by the failure of MYCN-amplified cells to efficiently utilize alternative forms of selenium/selenocysteine based uptake necessary for selenoprotein biosynthesis. Increased activity of one of such transporters, SLC7A11, in MYCN-amplified cells leads to cysteine overload, progressive mitochondrial decline and impaired proliferation. These data reveal in LRP8 a targetable, and specific vulnerability of MYCN-amplified neuroblastoma cells and disclose a yet-unaccounted mechanism for selective ferroptosis induction that has the potential to become an important therapeutic entry point for MYCN-amplified neuroblastoma. Statement of significanceGiven the largely unsuccessful repurposing of adult oncology drugs for the treatment of neuroblastoma, our discoveries pave the way for novel ferroptosis based strategies for this entity. Specifically, targeting of LRP8 may offer novel therapeutic and safer opportunities for a number of pediatric malignancies and MYCN driven cancers.

cancer biology↗

bioRxiv2018

A cell-density dependent metabolic switch sensitizes breast cancer cells to ferroptosis

Ferroptosis is a regulated form of necrotic cell death caused by iron-dependent phospholipid peroxidation. It can be induced by inhibiting glutathione peroxidase 4 (GPX4), the key enzyme for efficiently reducing peroxides within phospholipid bilayers. Recent data suggest that cancer cells undergoing EMT (dedifferentiation) and those resistant to standard therapy expose a high vulnerability toward ferroptosis. Although recent studies have begun to identify and characterize the metabolic and genetic determinants underlying ferroptosis, many mechanisms that dictate ferroptosis sensitivity remain unknown. Here, we show that low cell density sensitizes primary mammary epithelial and breast cancer cells to ferroptosis induced by GPX4 inhibition, whereas high cell density confers resistance. These effects occur irrespective of oncogenic signaling, cellular phenotype and expression of the fatty acid ligase acyl-CoA synthetase long chain family member 4 (ACSL4). By contrast, we show that a massive accumulation of neutral triacylglycerides (TAG) enriched with polyunsaturated fatty acids (PUFA) is induced at low cell density. In addition, de novo lipogenesis and desaturation pathways were found to be reduced at low cell density, indicative of increased fatty acid uptake. Our study suggests that PUFA-mediated toxicity is limited by the enrichment in TAGs that in turn might pose a vulnerability towards ferroptosis. Conclusively, cell density regulates lipid metabolism of breast epithelial and cancer cells, which results in a ferroptosis-sensitive cell state with the potential to be exploited therapeutically during metastatic dissemination.

cancer biology↗