📋 Browse Articles

This study investigates the application of machine learning techniques to predict the toxicity of tetrazole derivatives, aiding in the identification of environmental risks from chemical exposure. Utilizing LD50 data sourced from the scientific literature and the ChemIDplus database, regression models were developed to forecast acute intraperitoneal toxicity in mice. A machine learning regression model for acute intraperitoneal toxicity in mice was constructed and validated on a test dataset, achieving high accuracy (R2 = 0.76 and MSE below 10−4) and surpassing most of the comparable literature models. Molecular descriptors were computed via Mordred software to explore quantitative structure–activity relationships, and additionally, the model's robustness was demonstrated by measuring the acute toxicity of tetrazole derivatives synthesized through the azido-Ugi reaction. Show less

A new generation of backbone-functionalized NHC–gold( i ) complexes reveals ferroptosis through comprehensive mechanistic and biological investigation. Show less

The first comprehensive study of a series of seven mesoionic tetrazolylidene gold(I) chloride complexes (1-7) featuring a range of alkyl and aryl substituents (Me, t-Bu, iPr, Ph, Tol, Dipp, Mes) is reported. Three synthetic pathways enabling access to scarcely explored abnormal 1,3-disubstituted tetrazolium ligand precursors (L₁-L₇) have been established. All complexes are characterized by NMR spectroscopy, mass spectrometry, and elemental analysis, confirming their composition and purity. Single-crystal X-ray crystallography of six gold(I) complexes (1-6) reveals nearly linear coordination (176.49(11)-179.0(2)°) at the gold(I) center and a distinct geometric arrangement across the series. NMR stability studies with model nucleophiles L-cysteine (Cys) and glutathione (GSH) support the structural findings, demonstrating rapid and complete reaction of complexes 1-7 with thiols, as confirmed by ¹H NMR and ESI-MS. The antiproliferative activity of the obtained complexes (1-7) and selected precursors (L₂, L₃, L₅, L₇) has been evaluated using MTT assays against human A2780 (ovarian) and A549 (lung) cancer cell lines, alongside noncancerous VERO E6 kidney cells for comparison. Most of the complexes display high selectivity indices (SI^A2780 = 63.2-86.7) and potent antiproliferative effects in the low submicromolar range against A2780, outperforming cisplatin and matching the activity of auranofin. Overall, the results presented here demonstrate the potential of gold(I) tetrazolylidene-based complexes for medicinal applications. Show less

Mesoionic imines (MIIs) based on a 1,2,3-triazole core have been popularized in the past ca. 5 years. In this review article we discuss the synthesis, coordination ability and the structural and spectroscopic properties of this fascinating class of electronically ambivalent compounds. Apart from this, we also discuss the utility of MIIs and their compounds in directed C–H activation reactions, and in the activation and conversion of small molecules such as alkynes and CO2. Based on the current state of the art, we touch upon possible future developments of the chemistry of these classes of molecules. Show less

Abstract This article presents the synthesis and detailed structural investigation of a new palladium(II) heteroligand complex trans-[PdCl(CNXyl)2(C{CN(H)Xyl}2)]Cl, containing an acyclic diaminocarbene ligand and two isocyanide ligands. X-ray diffraction and NMR spectroscopy revealed that complex is stabilized both in the crystal and in solution by a system of N–H···Cl– hydrogen bonds formed between one chloride anion and two N–H groups of the diaminocarbene ligand (N–H···Cl–···H–N), with calculated energies of 3.8–5.4 kcal/mol. A Cambridge Structural Database search identified 22 other palladium(II) acyclic diaminocarbene complexes with similar N–H···X···H–N (X = Cl–, Br–, O=C<, O=S<, etc.) hydrogen-bonded systems. The complex demonstrated significant antiproliferative activity against the triple-negative breast cancer cell line MDA-MB-231, with an IC50 value of 5.55 ± 0.45 µM, which is four times higher than that of cisplatin. Show less

While various metal complexes demonstrate immunogenic cell death (ICD)-inducing properties, there is a lack of studies comparing ICD properties in structurally similar complexes with different metal centers. In this study, we synthesized four structurally similar Rh(I) and Ir(I) complexes with redox-active 1,2-bis(arylimino)acenaphthene (Ar-bian) ligands and assessed their anticancer and ICD-inducing properties. Analysis of damage-associated molecular patterns (DAMPs), ROS localization and dying cell populations highlighted the distinct roles of the metal center and the ligands. Specifically, only Rh(I) complexes induced the release of the three essential DAMPs and high levels of late apoptotic cells, while the Ir(I) complexes failed to trigger crucial “eat-me” signals. This work offers valuable insights into structure–activity relationships in metal complexes in the context of ICD. Show less

Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both the onset and progression of various diseases. Under physiological conditions, oxidative free radicals generated by the mitochondrial oxidative respiratory chain, endoplasmic reticulum, and NADPH oxidases can be effectively neutralized by NRF2-mediated antioxidant responses. These responses elevate the synthesis of superoxide dismutase (SOD), catalase, as well as key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption of this finely tuned equilibrium is closely linked to the pathogenesis of a wide range of diseases. Recent advances have broadened our understanding of the molecular mechanisms underpinning this dysregulation, highlighting the pivotal roles of genomic instability, epigenetic modifications, protein degradation, and metabolic reprogramming. These findings provide a foundation for exploring redox regulation as a mechanistic basis for improving therapeutic strategies. While antioxidant-based therapies have shown early promise in conditions where oxidative stress plays a primary pathological role, their efficacy in diseases characterized by complex, multifactorial etiologies remains controversial. A deeper, context-specific understanding of redox signaling, particularly the roles of redox-sensitive proteins, is critical for designing targeted therapies aimed at re-establishing redox balance. Emerging small molecule inhibitors that target specific cysteine residues in redox-sensitive proteins have demonstrated promising preclinical outcomes, setting the stage for forthcoming clinical trials. In this review, we summarize our current understanding of the intricate relationship between oxidative stress and disease pathogenesis and also discuss how these insights can be leveraged to optimize therapeutic strategies in clinical practice. Show less

RNA and proteins are two crucial players in the origin of life but while RNA evolved to assemble proteins from amino acids, a significant mirror-symmetric effect of amino acids to trigger the synthesis of RNA was missing. Here, the authors report ambient alkaline conditions where amino acids, without additional chemical activators, promote RNA copolymerisation more than 100-fold, starting from prebiotically plausible ribonucleoside-2′,3′-cyclic phosphates. Show less

Abstract Transition metal complexes have been widely utilized as cellular imaging tools. To impart organelle specificity, ligand architecture is usually modified to modulate properties like overall charge and lipophilicity. In many such designs, the metal identity and its intrinsic properties are often ignored. To address this gap, in this study, we explored the effects of changing the metal center on the localization patterns of isostructural complexes. To this end, we employed the thiosemicarbazone Dp44mT to synthesize coumarin‐conjugated complexes of Au(III), Pt(II), and Pd(II). Although the metal centers in these compounds share a formal d 8 configuration, they differ in properties such as ionic radius, charge density, and ligand exchange rates, which can affect their subcellular localization patterns. In addition, we synthesized a second set of analogous complexes using BODIPY as the conjugating fluorophore to assess the influence of using a different dye on the cellular distribution. Confocal imaging revealed that the complexes exhibited distinct intracellular distributions. For instance, while the coumarin‐conjugated Pt(II) complex localized specifically in lysosomes, the corresponding lipophilic Pd(II) complex lacked this specificity and instead followed a diffusely cytosolic distribution. Similarly, the more lipophilic BODIPY conjugated complexes were non‐specific in their cellular distribution as well. Overall, the findings of this study highlight the interplay of metal identity and lipophilicity in determining the localization patterns of Dp44mT‐based metal complexes, offering fresh insights into the design of new metal‐based imaging tools. Show less

ATP synthase, the enzyme responsible for regenerating adenosine triphosphate (ATP) in the cell, comprises a proton-translocating motor in the cell membrane (labeled FO in bacteria, mitochondria, and chloroplasts), coupled by a common stalk to a catalytic motor F1 that synthesizes or hydrolyzes ATP, depending on the direction of rotation. The detailed mechanisms of FO, F1 and their coupling in ATP synthase have been elucidated through structural studies, single-molecule experiments, and molecular modeling. The outcomes of this body of work are reviewed with a particular focus on the features of the mechanism that enable the high energy efficiency and reversibility of ATP synthase. Models for the origin of chemiosmosis involve either ATP synthesis (driven by the proton gradient across the membrane) or ATP hydrolysis (for pumping protons out of the cell) as a primary function, the other function being a later development enabled by the coupled nature of the two motors. The mechanism of ATP synthase and the stringent requirements on efficiency to maintain life constrain existing models and the search for the origin of chemiosmosis. Show less

Life is an exergonic chemical reaction. Many individual reactions in metabolism entail slightly endergonic steps that are coupled to free energy release, typically as ATP hydrolysis, in order to go forward. ATP is almost always supplied by the rotor-stator ATP synthase, which harnesses chemiosmotic ion gradients. Because the ATP synthase is a protein, it arose after the ribosome did. What was the energy currency of metabolism before the origin of the ATP synthase and how (and why) did ATP come to be the universal energy currency? About 27 % of a cell's energy budget is consumed as GTP during translation. The universality of GTP-dependence in ribosome function indicates that GTP was the ancestral energy currency of protein synthesis. The use of GTP in translation and ATP in small molecule synthesis are conserved across all lineages, representing energetic compartments that arose in the last universal common ancestor, LUCA. And what came before GTP? Recent findings indicate that the energy supporting the origin of LUCA's metabolism stemmed from H2-dependent CO2 reduction along routes that strongly resemble the reactions and transition metal catalysts of the acetyl-CoA pathway. Show less

This Review explores the state-of-the-art applications of artificial intelligence in small-molecule drug development, from target identification and drug synthesis up to clinical trial design and conduct. Show less

The direct and atom economic synthesis of azulenyl-substituted gold(i) carbene complexes, based on the modular template synthesis using gold(i) isonitrile complexes and amine nucleophiles, is presented. First, two azulenyl-substituted isonitriles as ligands were synthesized from a functionalizable azulene derivative, the latter stemming from a gold-catalyzed dimerization of internal alkynes. These azulene-bound gold(i) isonitrile complexes allow the smooth nucleophilic attack by both aliphatic and aromatic amines. The newly synthesized azulene-substituted gold(i) carbene complexes were evaluated for in vitro anticancer activity against multiple human cancer cell lines. Six lead compounds demonstrated potent and selective cytotoxicity, exceeding that of cisplatin by at least an order of magnitude in resistant and aggressive cancer models. Structure-activity relationship analysis revealed that specific ligand modifications, such as the position of the azulene moiety tethered to the carbene unit or nitrogen-bound ethyl or cyclic groups, are critical for enhancing the anticancer activity. Show less

Glycolysis stops where gluconeogenesis starts-at pyruvate, the central metabolite of biosynthesis. The early history of carbon metabolism is preserved in archaeal and bacterial enzymes for glucose synthesis and breakdown. Here, we summarize the distribution and phylogeny of enzymes involved in glycolysis, gluconeogenesis, and glycogen metabolism from genomes of cultured prokaryotes. The presence of glycolytic pathways in H2-dependent chemolithoautotrophs, including methanogens, which cannot grow on exogenous glucose, correlates with their use of glycogen for intracellular carbon storage. Glycogen synthesis and gluconeogenesis are universal among prokaryotes, but glycolysis is not, indicating that the enzymatic conversions of glycolysis arose in the gluconeogenic direction encompassing three phases: (1) an autotrophic origin from H2 and CO2 to pyruvate and triosephosphate (trunk glycolysis) fulfilling basic amino acid and cofactor synthesis in the last universal common ancestor, (2) from triosephosphate to glucose supplying cell wall (murein and pseudomurein) and nucleic acid biosynthetic requirements in the first free-living autotrophs, also giving rise to intracellular carbon reserves (glycogen), followed by (3) diversification and transfer of enzymes for glycogen-mobilizing glycolytic routes. An autotrophic origin of trunk glycolysis followed by glycogen-dependent origin of glucose utilization account for conservation, distribution, and diversity of enzymes observed in microbial sugar phosphate pathways. Show less

High-Grade Serous Ovarian Cancer (HGSOC) is the most common and lethal subtype of ovarian cancer, known for its high aggressiveness and extensive genomic alterations. Typically diagnosed at an advanced stage, HGSOC presents formidable challenges in drug therapy. The limited efficacy of standard treatments, development of chemoresistance, scarcity of targeted therapies, and significant tumor heterogeneity render this disease incurable with current treatment options, highlighting the urgent need for novel therapeutic approaches to improve patient outcomes. In this study we report a straightforward and stereoselective synthetic route to novel Pd(II)-vinyl and -butadienyl complexes bearing a wide range of monodentate and bidentate ligands. Most of the synthesized complexes exhibited good to excellent in vitro anticancer activity against ovarian cancer cells. Particularly promising is the water-soluble complex bearing two PTA (1,3,5-triaza-7-phosphaadamantane) ligands and the Pd(II)-butadienyl fragment. This compound combines excellent cytotoxicity towards cancer cells with substantial inactivity towards non-cancerous ones. This derivative was selected for further studies on ex vivo tumor organoids and in vivo mouse models, which demonstrate its remarkable efficacy with surprisingly low collateral toxicity even at high dosages. Moreover, this class of compounds appears to operate through a ferroptotic mechanism, thus representing the first such example for an organopalladium compound. Show less

Background/Objectives: The origin of genes and genetics is the story of the coevolution of translation systems and the genetic code. Remarkably, the history of the origin of life on Earth was inscribed and preserved in the sequences of tRNAs. Methods: Sequence logos demonstrate the patterning of pre-life tRNA sequences. Results: The pre-life type I and type II tRNA sequences are known to the last nucleotide with only a few ambiguities. Type I and type II tRNAs evolved from ligation of three 31 nt minihelices of highly patterned and known sequence followed by closely related 9 nt internal deletion(s) within ligated acceptor stems. The D loop 17 nt core was a truncated UAGCC repeat. The anticodon and T 17 nt stem-loop-stems are homologous sequences with 5 nt stems and 7 nt U-turn loops that were selected in pre-life to resist ribozyme nucleases and to present a 3 nt anticodon with a single wobble position. The 7 nt T loop in tRNA was selected to interact with the D loop at the "elbow". The 5'-acceptor stem was based on a 7 nt truncated GCG repeat. The 3'-acceptor stem was based on a complementary 7 nt CGC repeat. In pre-life, ACCA-Gly was a primitive adapter molecule ligated to many RNAs, including tRNAs, to synthesize polyglycine. Conclusions: Analysis of sequence logos of tRNAs from an ancient Archaeon substantiates how the pre-life to life transition occurred on Earth. Polyglycine is posited to have aggregated complex molecular assemblies, including minihelices, tRNAs, cooperating molecules, and protocells, leading to the first life on Earth. Show less

For life to emerge on Earth, peptides must first have formed without the aid of enzymes — but how? Reactions of sulfur-containing molecules might have been key. For life to emerge on Earth, peptides must first have formed without the aid of enzymes — but how? Reactions of sulfur-containing molecules might have been key. Show less

Submarine hydrothermal vents harbor diverse microbial communities and have long intrigued researchers studying the origin of life. Transition metals in these environments can be reduced by serpentinization, potentially forming zeolite-supported transition metal nanoparticles capable of driving prebiotic chemistry. This inorganic structure could catalyze biochemical reactions, including converting metabolically crucial pyruvate before the emergence of biological processes. This study explores the catalytic interconversion of pyruvate and lactate, mediated by lactate dehydrogenase in biochemical systems, using inorganic zeolite Y-supported Ni nanoparticles (Ni/Y) under mild hydrothermal vent conditions. Our results demonstrate that Ni/Y effectively catalyzes the hydrogenation of pyruvate in an inert environment, facilitated by the in situ generation of H₂ through an autocatalytic reaction between Ni/Y and H₂O. Post-reaction analysis by X-ray absorption spectroscopy (XAS) revealed structural transformations in the catalyst, including the formation of unique nickel oxide and hydroxide species, along with extra-framework aluminum from zeolite dealumination, resulting in a thin amorphous nickel oxide/hydroxide layer. Notably, Ni/Y also enables the oxidative reconversion of lactate to pyruvate under atmospheric conditions-an essential reaction catalyzed by lactate dehydrogenase in biological systems. These findings underscore the potential prebiotic role of Ni/Y, suggesting they may have catalyzed the synthesis of key metabolic intermediates. Show less

Tetrazoles are nitrogen-rich heterocycles that have attracted interest because of their numerous applications in pharmaceutical and medicinal chemistry. Four nitrogen atoms and one carbon atom make up these five-membered rings, which have special physicochemical and electrical characteristics, including acidity, resonance stabilization, and aromaticity. This article highlights the structure, spectroscopic characteristics, and physical and chemical characteristics of tetrazoles. It also describes how overlapping mechanisms, such as DNA replication inhibition, protein synthesis disruption, and oxidative stress induction, as well as similar therapeutic targets, enable inhibitors to serve as both antibacterial and anticancer agents. Tetrazole moieties have been fused with a range of pharmacophores, such as indoles, pyrazoles, quinolines, and pyrimidines, yielding fused derivatives that display substantial inhibitory activity against bacterial, fungal, and cancer cell lines, with certain compounds exhibiting efficacy comparable to or exceeding that of established therapeutic agents. The rational design of more efficacious tetrazole-based therapies is facilitated by structure-activity relationship analysis, which further highlights significant functional groups and scaffolds that contribute to increasing activity. We investigate the relationship between microbial inhibition and anticancer efficacy, opening up new avenues for the creation of multifunctional therapeutic agents. We hope that this study will offer significant guidance and serve as a valued resource for medicinal and organic researchers working on drug development and discovery in multifunctional therapeutics. The review involves a thorough investigation of tetrazole in recent years. Show less

Conditions that led to the synthesis of iron-sulfur clusters coordinated to tripeptides with a single thiolate ligand were investigated by UV-vis, NMR, EPR, and Mössbauer spectroscopies and by electrochemistry. Increasing concentrations of hydrosulfide correlated with the formation of higher nuclearity iron-sulfur clusters from mononuclear to [2Fe-2S] to [4Fe-4S] and finally to a putative, nitrogenase-like [6Fe-9S] complex. Increased nuclearity was also associated with decreased dynamics and increased stability. The synthesis of higher nuclearity iron-sulfur clusters is compatible with shallow, alkaline bodies of water on the surface of the early Earth, although other niche environments are possible. Because of the plasticity of such complexes, the type of iron-sulfur cluster formed on the prebiotic Earth would have been greatly influenced by the chemical environment and the thiolate containing scaffold. The discovery that all the major classes of iron-sulfur clusters easily form under prebiotically reasonable conditions broadens the chemistry accessible to protometabolic systems. Show less

Energy conservation is crucial to life's origin and evolution. The common ancestor of all cells used ATP synthase to convert proton gradients into ATP. However, pumps generating proton gradients and lipids maintaining proton gradients are not universally conserved across all lineages. A solution to this paradox is that ancestral ATP synthase could harness naturally formed geochemical ion gradients with simpler environmentally provided precursors preceding both proton pumps and biogenic membranes. This runs counter to traditional views that phospholipid bilayers are required to maintain proton gradients. Here, we show that fatty acid membranes can maintain sufficient proton gradients to synthesize ATP by ATP synthase under the steep pH and temperature gradients observed in hydrothermal vent systems. These findings shed substantial light on early membrane bioenergetics, uncovering a functional intermediate in the evolution of chemiosmotic ATP synthesis during protocellular stages postdating the ATP synthase's origin but preceding the advent of enzymatically synthesized cell membranes. Show less

Mitochondria are dynamic organelles that are essential for cellular energy generation, metabolic regulation, and signal transduction. Their structural complexity enables adaptive responses to diverse physiological demands. In cancer, mitochondria orchestrate multiple cellular processes critical to tumor development. Metabolic reprogramming enables cancer cells to exploit aerobic glycolysis, glutamine metabolism, and lipid alterations, supporting uncontrolled growth, survival, and treatment resistance. Genetic and epigenetic alterations in mitochondrial and nuclear DNA disrupt oxidative phosphorylation, tricarboxylic acid cycle dynamics, and redox homeostasis, driving oncogenic progression. Mitochondrial dysfunction in tumors is highly heterogeneous, influencing disease phenotypes and treatment responses across cancer types. Within the tumor microenvironment, mitochondria profoundly impact immune responses by modulating T-cell survival and function, macrophage polarization, NK cell cytotoxicity, and neutrophil activation. They also mediate stromal cell functions, particularly in cancer-associated fibroblasts and tumor endothelial cells. Although targeting mitochondrial function represents a promising therapeutic strategy, mitochondrial heterogeneity and adaptive resistance mechanisms complicate interventional approaches. Advances in mitochondrial genome editing, proteomics, and circulating mitochondrial DNA analysis have enhanced tumor diagnostic precision. This review synthesizes the developmental landscape of mitochondrial research in cancer, comprehensively summarizing mitochondrial structural dynamics, metabolic plasticity, signaling networks, and interactions with the tumor microenvironment. Finally, we discuss the translational challenges in developing effective mitochondria-based cancer interventions. Show less

Serpentinizing hydrothermal vents are likely sites for the origin of metabolism because they produce H2 as a source of electrons for CO2 reduction while depositing zero-valent iron, cobalt, and nickel as catalysts for organic reactions. Recent work has shown that solid-state nickel can catalyze the H2-dependent reduction of CO2 to various organic acids and their reductive amination with H2 and NH3 to biological amino acids under the conditions of H2-producing hydrothermal vents and that amino acid synthesis from NH3, H2, and 2-oxoacids is facile in the presence of Ni0. Such reactions suggest a metallic origin of metabolism during early biochemical evolution because single metals replace the function of over 130 enzymatic reactions at the core of metabolism in microbes that use the acetyl-CoA pathway of CO2 fixation. Yet solid-state catalysts tether primordial amino synthesis to a mineral surface. Many studies have shown that pyridoxal catalyzes transamination reactions without enzymes. Here we show that pyridoxamine, the NH2-transferring intermediate in pyridoxal-dependent transamination reactions, is generated from pyridoxal by reaction with NH3 (as little as 5 mm) and H2 (5 bar) on Ni0 as catalyst at pH 11 and 80 °C within hours. These conditions correspond to those in hydrothermal vents undergoing active serpentinization. The results indicate that at the origin of metabolism, pyridoxamine provided a soluble, organic amino donor for aqueous amino acid synthesis, mediating an evolutionary transition from NH3-dependent amino acid synthesis on inorganic surfaces to pyridoxamine-dependent organic reactions in the aqueous phase. Show less

Studies by microbiologists in the 1970s provided robust estimates for the energy supply and demand of a prokaryotic cell. The amount of ATP needed to support growth was calculated from the chemical composition of the cell and known enzymatic pathways that synthesize its constituents from known substrates in culture. Starting in 2015, geneticists and evolutionary biologists began investigating the bioenergetic role of mitochondria at eukaryote origin and energy in metazoan evolution using their own, widely trusted-but hitherto unvetted-model for the costs of growth in terms of ATP per cell. The more recent model contains, however, a severe and previously unrecognized error that systematically overestimates the ATP cost of amino acid synthesis up to 200-fold. The error applies to all organisms studied by such models and leads to conspicuously false inferences, for example that the synthesis of an average amino acid in humans requires 30 ATP, which no biochemistry textbook will confirm. Their ATP 'cost' calculations would require that E. coli obtains ~100 ATP per glucose and that mammals obtain ~240 ATP per glucose, untenable propositions that invalidate and void all evolutionary inferences so based. By contrast, established methods for estimating the ATP cost of microbial growth show that the first mitochondrial endosymbionts could have easily doubled the host's available ATP pool, provided (i) that genes for growth on environmental amino acids were transferred from the mitochondrial symbiont to the archaeal host, and (ii) that the host for mitochondrial origin was an autotroph using the acetyl-CoA pathway. Stated in simple terms, the significance of these findings are this: Life is a chemical reaction. It requires energy release in order to proceed. The currency of energy in cells is adenosine triphosphate, ATP. Five decades ago, microbiologists were able to measure and understand the amount of ATP that cells require to grow. New studies by evolutionary biologists have appeared in the meantime that brush aside the older microbiological findings, using their own methods to calculate the ATP cost of growth instead. Science is, however, an imperfect undertaking. The new studies contain a major error, similar to conflating centimeters with yards. The error affects many publications and their conclusions. Using the old methods, we can still meaningfully study the role of energy in evolution, including the origin of complex, nucleus-bearing cells. Show less

Aminoacyl-thiols reacting selectively with RNA diols over amine nucleophiles and demonstration of chemically controlled formation of peptidyl-RNA in water at neutral pH suggest an important role for thiol cofactors before the evolution of enzymes. Show less

Abstract Cancer cells rely heavily on de novo pyrimidine synthesis. Inhibiting pyrimidine metabolism directly suppresses tumor growth and fosters immune activation within the tumor microenvironment. Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the de novo pyrimidine synthesis pathway. Inhibiting DHODH can reverse immune suppression and trigger a mild innate immune response. However, the impact of DHODH inhibition on natural killer (NK) cells remains to be explored. In this study, we found that DHODH inhibition promoted NK cell infiltration into tumors efficiently. Mechanistically, DHODH suppression induced mitochondrial oxidative stress, leading to mitochondrial DNA (mtDNA) release into the cytoplasm through voltage-dependent anion channel (VDAC) oligomerization and caspase-3 activation. This subsequently activated the stimulator of interferon gene (STING) pathway, triggered ferroptosis, and induced gasdermin E (GSDME) mediated pyroptosis in cancer cells. These changes collectively facilitated NK cell recruitment. Furthermore, infiltrated NK cells enhanced GSDME-dependent pyroptosis in tumor cells through granzyme release, establishing a positive feedback loop that amplified anti-tumor immunity. Additionally, we developed EA6, a novel DHODH inhibitor that is more effective at promoting NK cell infiltration. In summary, this study reveals that targeting pyrimidine metabolism activates a novel mechanism involving pyroptosis-ferroptosis crosstalk and STING pathway activation to enhance NK cell-mediated immunity. These finding opens new avenues for enhancing the efficacy of targeted nucleotide metabolism in cancer therapy. Show less

In the framework of studies on protometabolism, Schlikker et al. characterized the conversion of pyridoxal to pyridoxamine under conditions mimicking the ones likely existing at the origin of metabolism. These conditions triggered nitrogen incorporation into amino acids in solution before the origins of enzymes. The suggested role for pyridoxal highlights its pivotal function in the transition from inorganic ammonia-dependent amino acid synthesis to organic reactions in aqueous solution and supports the "metabolism first" theory for biological evolution. Insights from the early evolution of natural enzymes can inspire the development of novel biocatalysts for biotechnological applications based on the catalytic versatility of pyridoxal. Show less

Mitochondria are bilayer membrane organelles with basic metabolic activity. They are considered hubs for biosynthesis, bioenergy, and signaling functions, coordinating major biological pathways. Mitochondria are coupled to the oxidation of fatty acids and pyruvate through electron transport chains and have historically been considered the primary source of cellular energy. Recent studies have depicted that mitochondria are centers that promote inflammatory responses and play a crucial role in combating pathogenic infections. Moreover, mitochondria provide the basis for tumor synthesis metabolism, control redox and calcium homeostasis, participate in transcriptional regulation, and control cell death. Mitochondria are involved in all steps of tumorigenesis. This review discusses the relationship between mitochondria (including mitochondrial metabolism and mitophagy) and tumors, and the relationship between mtDNA and inflammation, as well as its clinical application in inflammatory diseases. More importantly, the application and targeted treatment strategies provide more opportunities for the development of new anticancer drugs. Show less

Abstract The development of multifunctional carriers for gene delivery is a critical challenge in modern therapeutics, particularly in the context of multi‐drug therapy (MDT). In this study, we report the synthesis and characterization of fluorinated guanidino‐polyamine conjugates based on low‐generation polyamidoamine (PAMAM) dendrimers and low molecular weight polyethyleneimine (PEI) polymers. These conjugates are designed to act as both efficient transfection agents and artificial ribonucleases, providing a dual‐function approach to gene therapy. The functionalization with fluorinated guanidino groups enhances DNA condensation, facilitates intracellular delivery, and enables tracking via 19 F MRI. Potentiometric and kinetic studies demonstrate their phosphodiesterase activity on a model compound, with PAMAM G4 derivatives exhibiting the highest catalytic efficiency. Biolayer interferometry and transfection experiments confirm mRNA cleavage activity, leading to reduced gene expression. Additionally, transfection studies with plasmid DNA (pDNA) indicate high gene delivery efficiency, surpassing conventional PEI‐based systems while maintaining low cytotoxicity. These findings suggest that the conjugates presented herein, and in particular those derived from low‐generation PAMAM dendrimers, can serve as promising multifunctional carriers for a combined diagnostic and MDT, offering a new strategy for synergistic gene delivery and RNA degradation. Show less