Biology subjects

Filipovic, M. R.

Publications and source records attributed to Filipovic, M. R..

3 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↗

bioRxiv2023

Protein tyrosine phosphatase receptor kappa regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity

Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). Here we report that obesity leads to dysregulated expression of hepatic protein-tyrosine phosphatases (PTPs). PTPRK was found to be increased in steatotic hepatocytes in both humans and mice, and positively correlated with PPAR{gamma}-induced lipogenic signalling. High-fat-fed PTPRK knockout mice displayed reduced weight gain and hepatic fat accumulation. Phosphoproteomic analysis in primary hepatocytes and hepatic metabolomics identified fructose-1,6-bisphosphatase 1 and glycolysis as PTPRK targets in metabolic reprogramming. Silencing PTPRK in hepatoma cell lines resulted in reduced colony-forming ability and PTPRK knockout mice developed smaller tumours after diethylnitrosamine-induced hepatocarcinogenesis. Our study defines a novel role for PTPRK in regulating hepatic glycolysis, lipid metabolism, and tumour development. PTPRK inhibition may provide therapeutic possibilities in obesity-associated liver diseases. HighlightsO_LIHepatic receptor-type PTPs are increased in MASLD C_LIO_LIPTPRK is expressed in hepatocytes and upregulated in obesity C_LIO_LIPTPRK deficiency reduces body fat mass and liver steatosis in diet-induced obesity C_LIO_LIPTPRK regulates hepatic glycolysis and lipogenesis, promoting tumorigenesis C_LI

cancer biology↗

bioRxiv2017

H2S mediates interbacterial communication through the air reverting intrinsic antibiotic resistance

Hydrogen sulfide, a gas classically considered as a by-product of cellular metabolism, is today recognized as a crucial gasotransmitter in Eukaryotes. Moreover, most bacteria harbor the eukaryotic orthologous genes for H2S synthesis, and these genes have been linked to different metabolic pathways.\n\nSome bacteria, however, produce high amounts of H2S in their extracellular space, a characteristic classically used for identification purposes. This is the case of Salmonella Typhimurium, which produces H2S by its phsABC operon. Here we show that extracellular release of H2S by S. Typhimurium is solely dependent on its phsABC operon. Furthermore, we show that S. Typhimurium and other H2S-producing bacteria can interact with physically distant bacteria through H2S production. We demonstrate how H2S can revert intrinsic cephalosporin resistance of Enterococccus faecalis and Enterococcus faecium to complete susceptibility. This study constitutes a significant step in the study of bacterial interplay and niche competition. Furthermore, as H2S releasing drugs have already been designed, our results open the way to future therapeutic alternatives for the treatment of infections caused by enterococci, multiresistant pathogens for which no treatments are clinically available.\n\nAuthor SummaryIt has been known for decades that bacteria can communicate with each other through the diffusion of metabolites in the media. However, the capacity of a bacterium to interact with other physically distant cell is a recent discovery of the 21st century. In this work we show how some well-studied bacteria, as it is Salmonella spp., interacts with other bacteria thanks to the compound hydrogen sulfide (H2S) that they produce and release to the environment.\n\nIn our study we have designed novel techniques that allow us to study the interaction between two bacteria, and we have seen that Salmonella is able to affect other species that is even 1 cm away, i.e., a distance corresponding to 10.0000 times its own size.\n\nWhat is more astonishing is that Enterococcus, when exposed to the H2S, is dramatically becomes susceptible to many antibiotics, to which it is supposed to be naturally resistant. Enterococcus spp. are responsible for life-threatening infections in hospitals worldwide. Thus, our observations reveal that bacteria can communicate through the air with H2S, and that this molecule can make bacteria that are highly resistant to antibiotics susceptible to antibiotics, making untreatable infections treatable with current antibiotics.

microbiology↗