Biology subjects

Alborzinia, H.

Publications and source records attributed to Alborzinia, H..

6 recordsLinked to original sources

bioRxiv2025

Sodium Aurothiomalate Induces Ferroptosis by Targeting GPX4 via Gold-Dependent Thiomalate Covalent Modification

Ferroptosis, an iron-dependent form of oxidative cell death, is predominantly regulated by glutathione peroxidase 4 (GPX4), making it a promising target for cancer therapy. However, the majority of GPX4 inhibitors, most of which contain a chloroacetamide moiety such as RSL3, are limited by poor pharmacokinetic properties and off-target effects, hindering their preclinical translation. Utilizing a range of interdisciplinary methodologies, we show that sodium aurothiomalate (ATM), a drug approved by many agencies, induces ferroptosis by covalently targeting GPX4 via formation of a selenenylsulfide bond. In preclinical models of neuroblastoma and acute myeloid leukemia (AML), ATM combined with ferric ammonium citrate (FAC) yields a synergistic effect, resulting in a significant reduction in tumor growth. Mechanistically, ATM disrupts GPX4 activity by covalently binding thiomalate to the active site selenocysteine, while modification of specific cysteine residues leads to destabilization of the protein and impaired binding to phospholipids. We propose that these covalent modifications are achieved through a unique reaction mechanism, in which the gold component of ATM acts as a thiol-masking carrier and is only transiently present, being subsequently displaced and allowing the reaction of the thiomalate moiety with the target selenocysteine or cysteine. Our data lay the foundation for development of novel, drug-like thiol-based GPX4 inhibitors.

biochemistry↗

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

Differential KEAP1/NRF2 mediated signaling widens the therapeutic window of redox-targeting drugs in SCLC therapy

Small cell lung cancer (SCLC) patients frequently experience a remarkable response to first-line therapy. Follow up maintenance treatments aim to control residual tumor cells, but generally fail due to cross-resistance, inefficient targeting of tumor vulnerabilities, or dose-limiting toxicity, resulting in relapse and disease progression. Here, we show that SCLC cells, similar to their cells of origin, pulmonary neuroendocrine cells (PNECs), exhibit low activity in pathways protecting against reactive oxygen species (ROS). When exposed to a novel thioredoxin reductase 1 (TXNRD1) inhibitor, these cells quickly exhaust their ROS-scavenging capacity, regardless of their molecular subtype or resistance to first-line therapy. Importantly, unlike non-cancerous cells, SCLC cells cannot adapt to drug-induced ROS stress due to the suppression of ROS defense mechanisms by multiple layers of epigenetic and transcriptional regulation. By exploiting this difference in oxidative stress management, we safely increased the therapeutic dose of TXNRD1 inhibitors in vivo by pharmacological activation of the NRF2 stress response pathway. This resulted in improved tumor control without added toxicity to healthy tissues. These findings underscore the therapeutic potential of TXNRD1 inhibitors for maintenance therapy in SCLC. Graphical summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=72 SRC="FIGDIR/small/621846v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@2a7336org.highwire.dtl.DTLVardef@f21de9org.highwire.dtl.DTLVardef@189d062org.highwire.dtl.DTLVardef@cff38b_HPS_FORMAT_FIGEXP M_FIG C_FIG Pharmacological induction of NRF2 leads to differential cyto-protection against TXNRD1 inhibitors in normal tissue but not in SCLC tumor cells. This results in a reduction of adverse effects, allowing to increase the therapeutic dose.

cancer 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↗

bioRxiv2023

Low level of antioxidant capacity biomarkers but not target overexpression predicts vulnerability to ROS-inducing drugs

Despite a strong rationale for why cancer cells are susceptible to redox-targeting drugs, such drugs often face tumor resistance or dose-limiting toxicity in preclinical and clinical studies. An important reason is the lack of specific biomarkers to better select susceptible cancer entities and stratify patients. Using a large panel of lung cancer cell lines, we identified a set of "antioxidant-capacity" biomarkers (ACB), which were tightly repressed, partly by STAT3 and STAT5A/B in sensitive cells, rendering them susceptible to multiple redox-targeting and ferroptosis-inducing drugs. Contrary to expectation, constitutively low ACB expression was not associated with an increased steady state level of reactive oxygen species (ROS) but a high level of nitric oxide, which is required to sustain high replication rates. Using ACBs, we identified cancer entities with a high percentage of patients with favorable ACB expression pattern, making it likely that more responders to ROS-inducing drugs could be stratified for clinical trials.

cancer biology↗

bioRxiv2021

MYCN mediates cysteine addiction and sensitizes to ferroptosis

Aberrant expression of MYC family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYC induces massive lipid peroxidation upon depletion of cysteine, the rate-limiting amino acid for glutathione biosynthesis and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and irondependent type of cell death. In MYCN-amplified childhood neuroblastoma, MYCN mediates resistance to ferroptosis by activating transsulfuration of methionine to cysteine. MYCN may contribute to spontaneous tumor regression in low-risk neuroblastomas by promoting ferroptosis in cells with epigenetically silenced cystathionine-beta-synthase, the rate-limiting enzyme for transsulfuration. We identified enzymes and antiporter proteins crucial to ferroptotic escape, providing multiple previously unknown sites that may be acted on therapeutically.

cancer biology↗