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Oxidation-reduction (redox) reactions are fundamental to sustaining life, with reactive oxygen and nitrogen species playing pivotal roles in cellular signaling and homeostasis. However, excessive oxidative stress disrupts redox balance, contributing to a wide range of diseases, including inflammatory and pulmonary disorders, neurodegeneration, and cancer. Although numerous antioxidant therapies have been developed and tested for oxidative stress-related diseases, their clinical efficacy remains limited. Here, we introduce the emerging concept of 'supersulfides', a class of redox molecule species with unique antioxidant and nucleophilic properties, which have recently been recognized as crucial regulators of cellular redox homeostasis. Unlike traditional antioxidants, supersulfides offer novel mechanisms of action that directly target the underlying processes of oxidative stress. This review summarizes current knowledge on supersulfides, highlighting their roles in oxidative stress and associated diseases, as well as the mechanisms underlying oxidative stress-related pathology. The therapeutic potential of synthetic supersulfides for treating oxidative stress-related diseases is also discussed. A comprehensive understanding of the molecular and cellular basis of redox biology can help to guide the development of innovative redox-based therapeutic strategies aimed at preventing and treating diseases associated with disturbed redox regulation. Show less

Redox, a native modality in biology involving the flow of electrons, energy, and information, is used for energy-harvesting, biosynthesis, immune-defense, and signaling. Because electrons (in contrast to protons) are not soluble in the medium, electron-flow through the redox modality occurs through redox reactions that are sometimes organized into pathways and networks (e.g., redox interactomes). Redox is also accessible to electrochemistry, which enables electrodes to receive and transmit electrons to exchange energy and information with biology. In this Perspective, efforts to develop electrochemistry as a tool for redox-based bio-information processing: to interconvert redox-based molecular attributes into interpretable electronic signals, are described. Using a series of Case Studies, how the information-content of the measurements can be enriched using: diffusible mediators; tuned electrical input sequences; and cross-modal measurements (e.g., electrical plus spectral), is shown. Also, theory-guided feature engineering approaches to compress the information in the electronic signals into quantitative metrics (i.e., features) that can serve as correlating variables for pattern recognition by data-driven analysis are described. Finally, how redox provides a modality for electrogenetic actuation is illustrated. It is suggested that electrochemistry's capabilities to provide real-time, low-cost, and high-content data in an electronic format allow the feedback-control needed for autonomous learning and deployable sensing/actuation. Show less

An analysis of dose, dose frequency, human pharmacokinetics, and potential drug-drug interactions (DDI) was performed on small-molecule oral drugs approved by the FDA from 2020 to 2024 (n = 104). Although most oral drugs are administered QD (67%), BID and TID regimens are also regularly approved (32%). First-in-class (FIC) drugs and drugs with Orphan Drug Designation (ODD) have a higher frequency of BID or TID administration compared to drugs without those designations (BID and TID = 50% for FIC drugs vs 19% for non-FIC; BID and TID = 41% for ODD vs 20% non-ODD). Most drugs are >95% plasma protein bound (58%), with a large fraction >99% bound (29%). Of these drugs, 22% have black box warnings and 42% list contraindications. An examination of DDI revealed the most frequent warning around CYP3A4 induction (60%). These findings will help medicinal chemists better understand and predict typical and nontypical profiles of oral drugs. Show less

Computational metabolomics will be established in drug discovery and research on complex biological networks. This field of research enhances the detection of metabolic biomarkers and the prediction of molecular interactions by combining multiscale analysis with in silico and molecular docking methods. These include nuclear magnetic resonance, mass spectrometry, and innovative bioinformatics, which enable the accurate generation and characterization of metabolomes. Molecular docking is a crucial tool for simulating the interaction between ligands and receptors, thereby facilitating the identification of potential therapeutics. It also discusses the potential of metabolomics to inform drug modes of action, from pharmacokinetics to forecasting toxicity, thereby streamlining drug development pipelines. We highlight applications in anticancer, antimicrobial, and antiviral drug discovery and explain how these computational models can accelerate target validation and enhance the accuracy of therapeutic strategies. In addition, this review addresses the current challenges and future directions for computational techniques in conjunction with experimental data to advance personalized medicine. In conclusion, this review aims to highlight the prospective approaches of computational metabolomics and molecular docking that identify evolutionary adaptive metabolisms of multiscale biological systems through their synergistic utilization to overcome the key hurdles involved in both drug discovery and metabolomic research. Show less

Ferredoxins (FDXs) are evolutionarily conserved iron-sulfur (Fe-S) proteins that serve as master regulators of mitochondrial redox homeostasis, governing critical processes including electron transfer, energy metabolism, Fe-S cluster biogenesis, and steroidogenesis. In humans, the mitochondrial isoforms FDX1 and FDX2 exhibit specialized yet complementary functions: FDX1 directs steroidogenesis, protein lipoylation, and copper redox cycling, while FDX2 is a core factor in Fe-S cluster assembly. Crucially, dysregulation of these proteins disrupts mitochondrial integrity, impairs redox balance, and activates multiple programmed cell death (PCD) pathways such as cuproptosis, ferroptosis, apoptosis, and autophagic cell death. This review systematically analyzes their isoform-specific roles in mitochondrial electron transport, Fe-S cluster dynamics, metabolic regulation, and summarizes major advances in understanding how FDX1 and FDX2 orchestrate mitochondrial-PCD crosstalk. The work further examines their critical functions in PCD execution, including FDX1-mediated cuproptosis through Cu+-dependent aggregation of lipoylated proteins and FDX2-deficiency-driven ferroptosis via Fe-S cluster collapse and iron overload. Disease mechanisms across multiple pathologies, including cancer, neurodegeneration, cardiovascular disease, endocrine disorders, and genetic syndromes, are explored, highlighting links to FDX dysfunction, with emerging therapeutic strategies targeting FDXs also addressed. By elucidating the synergistic roles of FDX1 and FDX2 as metabolic-death gatekeepers, this review establishes a foundation for developing isoform-targeted therapies against diverse pathologies. Show less

In this Review, Emerling and colleagues summarize the roles of phosphatidylinositol 4-kinases (PI4Ks) and phosphatidylinositol phosphate kinases (PIPKs) in cancer. They highlight the altered expression of these kinases in tumours and discuss ongoing efforts in developing therapies targeting these lesser-studied phosphoinositide kinase families. Show less

AbstractWe report the development of an efficient and versatile synthetic protocol for the preparation of gold(I) and palladium(II) complexes bearing N‐heterocyclic carbene (NHC) thioglucosides and their azolium precursors. Gold(I) and Nolan‐type palladium(II)‐allyl complexes were synthesized under mild aerobic conditions using potassium carbonate as a base. Additionally, allyl palladate complexes were prepared via a straightforward solvent‐free method. In vitro assays on three ovarian cancer cell lines (OVCAR‐5, A2780, and its cisplatin‐resistant clone A2780cis) revealed interesting structure‐activity relationships (SARs). Gold(I) complexes with saturated NHC ligands showed enhanced activity, while Nolan‐type palladium(II)‐allyl complexes with unsaturated NHC ligands exhibited higher efficacy. Allyl palladates demonstrated similar activity regardless of whether the ligand was saturated or not. The most promising compounds display high selectivity for cancer cells, with cytotoxicity comparable to cisplatin on A2780 and OVCAR‐5 lines and superior activity against the A2780cis line. Notably, these compounds showed minimal toxicity towards non‐cancerous MRC‐5 cells. This selective anticancer activity is likely due to the presence of glucoside units, suggesting their role as targeting agents. TLDR: The most promising compounds display high selectivity for cancer cells, with cytotoxicity comparable to cisplatin on A2780 and OVCAR‐5 lines and superior activity against the A2780cis line. Show less

Background

Patients with colorectal cancer (CRC) harboring BRAF mutation have a poor prognosis. The median survival time for patients with advanced BRAF^V600E-mutant CRC is only approximately one year. Owing to the insensitivity to standard chemotherapy, there are still no effective and highly specific treatment strategies available in clinical practice for CRC patients with BRAF mutation. Therefore, targeting the BRAF^V600E mutation site, researching and exploring novel targeted therapies are essential to improve the survival rate of patients with this CRC subtype.

Aim

This study aims to develop a precise therapeutic system for BRAF^V600E CRC, based on the carrier properties of extracellular vesicles (EVs) and gene therapy targeting BRAF^V600E.

Method

We first obtained engineered cells capable of stably producing EVs loaded with BRAF^V600E nucleic acid drugs (siBRAF^V600E). Next, BRAF^V600E-mutant and wild-type CRC cell lines, as well as corresponding subcutaneous and metastasis models, were used to evaluate the therapeutic efficacy of EVs-siBRAF^V600E and explored the mechanism. Notably, patient-derived xenograft (PDX) models, which share the same molecular characteristics, pathological features, and heterogeneity as patients do, were utilized to further explore the therapeutic efficacy and mechanisms.

Result

EVs-siBRAF^V600E specifically inhibited BRAF^V600E CRC but didn't affect BRAF wild-type CRC in vitro and vivo. EVs-siBRAF^V600E exerts its therapeutic effect by regulating the MEK1/2-ERK1/2 pathway, and it has demonstrated excellent therapeutic efficacy in PDX models.

Conclusion

The therapeutic EVs we constructed are effective and specific for the BRAF^V600E-mutant CRC. This study provides a novel strategy for the treatment of CRC patients with BRAF^V600E mutation. Show less

TLDR: Investigation of anticancer and antitrypanosomatid activities of eight monoanionic metal bis(dithiolene) complexes showed that [Ph4P][Pt(tBu-thiazdt)2] and [Ph4P][Pd(tBu-thiazdt)2] complexes might have potential as novel anticancer and antitrypanosomatid agents as alternatives to current therapeutics. Show less

Abstract We present a comprehensive study on the chemical reactivity in the gas phase, with amino acids and peptides, and in the cell, the anticancer activity and localization of a series of seven cationic biphenyl gold(III) complexes with aryl, alkyl, and chiral diphosphine ancillary ligands. Despite some structural differences, all the complexes similarly featured high stability toward reduction or ligand exchange in cell‐free conditions. The biphenyl Au(III) complex including the 1,2‐diphenylphosphinoethane (dppe) ligand manifested the same high stability in a cellular setting, as attested by a combination of cryo‐Synchrotron Radiation‐X‐Ray Fluorescence (cryo‐SR‐XRF) nano‐imaging and cryo‐Synchrotron Radiation‐X‐ray Absorption Spectroscopy (cryo‐SR‐XAS) measurements. Tandem cryo‐SR‐XRF elemental mapping and confocal fluorescence microscopy demonstrated the selective accumulation of the dppe complex in mitochondria. This represents the first study of the speciation and distribution of an organogold(III) complex in cancer cells. Show less

Title: Radiosensitization effect of iridium (III) complex on lung cancer cells via mitochondria apoptosis pathway. Abstract: BACKGROUND: Lung cancer is the leading cause of cancer-related death in the worldwide. Although cisplatin and other platinum-based drugs are widely used as radiosensitizers in radiotherapy and considered the first-line treatment for advanced lung cancer, their clinical utility is often limited by drug resistance and severe cytotoxic side effects. In recent years, iridium-based complexes and other transition metal cation complexes with similar structural properties have garnered increasing research interest due to their potential anticancer properties. METHODS: Recently, we synthesized a novel iridium (III) complex (Ir-1) and evaluated its safety and stability. The present study aimed to identify Ir-1 with potent anticancer activity by assessing its cytotoxic effects on lung cancer cells in vitro. Additionally, it investigated Ir-1's radiosensitizing efficacy and the underlying mechanisms. RESULTS: The results demonstrated that Ir-1 exhibited significant radiosensitizing effects on lung cancer cells. Ir-1 effectively reduced cell viability and colony formation, arrested the cell cycle at the G2/M phase, inhibited cell migration and invasion, decreased mitochondrial membrane potential, and increased reactive oxygen species (ROS) generation in lung cancer cells. Importantly, these cytotoxic effects were selective, with minimal impact on normal cells. Mechanistic studies showed that Ir-1 enhanced radiation-induced cancer cell death by disrupting mitochondrial function and activating the mitochondrial apoptotic pathway. This was evidenced by upregulated expression levels of Bax, Cytochrome c (Cyt-C), and Caspase9 proteins, along with reduced level of Bcl-2 protein. Notably, the addition of a Cyt-C inhibitor significantly reduced the expression of Cyt-C and Caspase9 proteins. Similarly, treatment with the Caspase9 inhibitor Z-LEHD-FMK also reduced Caspase9 protein level. CONCLUSION: This study provides robust evidence that Ir-1 is a promising and safe radiosensitizer for lung cancer therapy. Its ability to enhance radiation-induced cytotoxicity through mitochondrial dysfunction and activation of apoptotic pathways highlights its potential for clinical application. Show less

A branch of the nucleotide excision repair (NER) pathway, transcription-coupled repair (TCR or TC-NER) specifically operates on the template DNA strand of actively transcribed genes. Initiated by stalling of elongating RNA polymerase complexes at damaged sites, TC-NER has historically been viewed as "accelerated repair", arguably necessary for the maintenance of vital transcription function. Conversely, the conventional "global genome" (GG-NER) mechanism, operating throughout the genome, is usually regarded as a much slower process, even though it has long been found that differences in repair kinetics between transcribed DNA and the rest of the genome are not manifested for all structural types of DNA damage. Considering that damage detection is the rate-limiting step of overall repair reactions in most cases and that the mechanisms of the initial recognition of modified DNA structure are fundamentally different between TC-NER and GG-NER, it is suggestive to attribute the observed kinetic differences to different damage spectra recognized by the two pathways. This review summarizes current knowledge on the differential requirements of TC-NER and GG-NER towards specific damage types, based on their structural rather than spatial characteristics, and highlights some common features of DNA modifications repaired preferentially or exclusively by TC-NER, while evading other repair mechanisms. Show less

BACKGROUND: Drug repositioning is a pivotal strategy in pharmaceutical research, offering accelerated and cost-effective therapeutic discovery. However, biomedical information relevant to drug repositioning is often complex, dispersed, and underutilized due to limitations in traditional extraction methods, such as reliance on annotated data and poor generalizability. Large language models (LLMs) show promise but face challenges such as hallucinations and interpretability issues. OBJECTIVE: This study proposed long chain-of-thought for drug repositioning knowledge extraction (LCoDR-KE), a lightweight and domain-specific framework to enhance LLMs' accuracy and adaptability in extracting structured biomedical knowledge for drug repositioning. METHODS: A domain-specific schema defined 11 entities (eg, drug, disease) and 18 relationships (eg, treats, is biomarker of). Following the established schema architecture, we constructed automatic annotation based on 10,000 PubMed abstracts via chain-of-thought prompt engineering. A total of 1000 expert-validated abstracts were curated into a drug repositioning corpus, a high-quality specialized corpus, while the remaining entries were allocated for model training purposes. Then, the proposed LCoDR-KE framework combined supervised fine-tuning of the Qwen2.5-7B-Instruct model with reinforcement learning and dual-reward mechanisms. Performance was evaluated against state-of-the-art models (eg, conditional random fields, Bidirectional Encoder Representations From Transformers, BioBERT, Qwen2.5, DeepSeek-R1, OpenBioLLM-70B, and model variants) using precision, recall, and F1-score. In addition, the convergence of the training method was assessed by analyzing performance progression across iteration steps. RESULTS: LCoDR-KE achieved an entity F1 of 81.46% (eg, drug 95.83%, disease 90.52%) and triplet F1 of 69.04%, outperforming traditional models and rivaling larger LLMs (DeepSeek-R1: entity F1=84.64%, triplet F1=69.02%). Ablation studies confirmed the contributions of supervised fine-tuning (8.61% and 20.70% F1 drop if removed) and reinforcement learning (6.09% and 14.09% F1 drop if removed). The training process demonstrated stable convergence, validated through iterative performance monitoring. Qualitative analysis of the model's chain-of-thought outputs showed that LCoDR-KE performed structured and schema-aware reasoning by validating entity types, rejecting incompatible relations, enforcing constraints, and generating compliant JSON. Error analysis revealed 4 main types of mistakes and challenges for further improvement. CONCLUSIONS: LCoDR-KE enhances LLMs' domain-specific adaptability for drug repositioning by offering an open-source drug repositioning corpus and a long chain-of-thought framework based on a lightweight LLM model. This framework supports drug discovery and knowledge reasoning while providing scalable, interpretable solutions applicable to broader biomedical knowledge extraction tasks. Show less

Electron transfer coupled to redox chemistry is at the heart of metabolism. The proteins responsible for moving electrons (protein electron carriers) must have emerged at the origin of life. The small iron-sulfur-binding bacterial ferredoxins were likely among these first proteins. Embedded within the ferredoxin sequence and structure is a symmetry that points to an ancient gene duplication event. Little is understood about the nature of ferredoxins prior to this duplication event or what environmental factors may have driven the selection for more complex forms. The deep-time molecular history of ferredoxins goes back billions of years and cannot be reconstructed by phylogenetic analyses based on amino acid sequences. Here, we use structure-guided protein design to model a fossil half-ferredoxin stage in the evolution of this fold, the semidoxins, and their symmetric full-length counterparts, the symdoxins. Semidoxin designs homodimerize, exhibiting structural, thermodynamic, and electrochemical behaviors in most cases identical to cognate symdoxins. However, the semi- and symdoxin fossil stages behave differently when incorporated into an in vivo electron transfer complementation assay. Both can support bacterial growth dependent on protein expression. Growth rates of bacteria expressing the semidoxins are much more sensitive to oxygen than those of bacteria expressing symdoxins. Motivated by the in vivo functionality of designed semidoxins, we identified putative naturally occurring semidoxins in extant anaerobic microorganisms. This is consistent with the observed in vivo oxygen sensitivity of the semidoxin designs. One natural semidoxin is shown to be folded and redox active. However, it exists as a mixture of monomers and dimers, suggesting a potential connection between semidoxins and even simpler single iron-sulfur cluster-binding peptides. Show less

Cytochrome c (Cytc) is a multifunctional protein, essential for respiration and intrinsic apoptosis. Post-translational modifications of Cytc have been linked to physiological and pathophysiologic conditions, including cancer. Cytc tyrosine 67 (Y67) is a conserved residue that is important to the structure and function of Cytc. We here report the phosphorylation of Y67 of Cytc purified from bovine heart mapped by mass spectrometry. We characterized the functional effects of Y67 Cytc modification using in vitro and cell culture models. Y67 was mutated to the phosphomimetic glutamate (Y67E) and to phenylalanyl (Y67F) as a control. The phosphomimetic Y67E Cytc inhibited cytochrome c oxidase (COX) activity, redirecting energy metabolism toward glycolysis, and decreased the pro-apoptotic capabilities of Cytc. The phosphomimetic Y67E Cytc showed a significantly impaired rate of superoxide scavenging and a reduced rate of oxidation by hydrogen peroxide, suggesting a lower ability to transfer electrons and scavenge reactive oxygen species (ROS). Phosphomimetic Y67E replacement led to an almost complete loss of cardiolipin peroxidase activity, pointing to a central role of Y67 for this catalytic function of Cytc. In intact cells, phosphomimetic replacement leads to a reduction in cell respiration, mitochondrial membrane potential, and ROS levels. We propose that Y67 phosphorylation is cardioprotective and promotes cell survival. 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

Ewing sarcoma (EwS) cell line culture largely relies on standard techniques, which do not recapitulate physiological conditions. Here, we report on a feasible and cost-efficient EwS cell culture technique with increased physiological relevance employing an advanced medium composition, reduced fetal calf serum, and spheroidal growth. Improved reflection of the transcriptional activity related to proliferation, hypoxia, and differentiation in EwS patient tumors was detected in EwS cells grown in this refined in vitro condition. Moreover, transcriptional signatures associated with the oncogenic activity of the EwS-specific FET::ETS fusion transcription factors in the refined culture condition were shifted from proliferative toward metabolic gene signatures. The herein-presented EwS cell culture technique with increased physiological relevance provides a broadly applicable approach for enhanced in vitro modeling relevant to advancing EwS research and the validity of experimental results. Show less

Influenza A viruses (IAVs) are single-stranded negative-sense RNA viruses that continually challenge animal and human health. In IAV-infected cells, host RNA-binding proteins play key roles in the life cycle of IAV by directly binding to viral RNA. Here, we examined the role of the host RNA-binding protein nucleophosmin-1 (NPM1) in IAV replication. We found that, as a nucleolar phosphoprotein, NPM1 directly binds to viral RNA (vRNA) and inhibits the replication of various subtypes of IAV. NPM1 binding to vRNA competitively reduces the assembly of the viral ribonucleoprotein complex and the viral polymerase activity, thereby reducing the generation of progeny viral RNA and virions. The RNA-binding activity of NPM1, with the key residues T199, T219, T234, and T237, is essential for its anti-influenza function. Taken together, our findings demonstrate that NPM1 acts as an RNA-binding protein and interacts with IAV vRNA to suppress viral replication. Show less

The diversification of ligands provides more opportunities to adjust the photophysical performance as well as the bio-function of Ru(II) complexes as novel photosensitizers. Herein, a kind of Ru(II) complexes carrying resveratrol derivative, amino-Res, as ligand was designed and synthesized. The representative complex (named Ru4) showed potent anticancer activity under the trigger of 520 nm-light. Lipophilicity and cellular accumulation experiments indicated that Ru4 possessed higher LogP_O/W value and cell up-take than Ru1-Ru3 and [Ru(bpy)₃]²⁺. Mechanism study revealed that Ru4 could inhibit cancer cell migration, invasion and cancer stemness. The bio-function of Ru4 was mainly inherited from the amino-Res ligand. The in vivo study demonstrated that Ru4 could inhibit the tumor growth without significant system toxicity. Show less

S: Mercury ions (Hg²⁺) are highly toxic and prone to bioaccumulation, showing a strong attraction to proteins and enzymes that contain sulfur. Even minute quantities of Hg²⁺ can lead to severe health issues. Given that mitochondria are a primary target organelle of Hg²⁺, it is essential to create a probe that can accurately detect Hg²⁺ within intracellular mitochondria. In this study, we developed two innovative Ir(III) complex probes that emit near-infrared light. The crystal structure of Ir2 was determined using X-ray techniques, which reveals that Ir2 contains a pyridine group capable of recognizing Hg²⁺ and targeting mitochondria, allowing for the precise identification of Hg²⁺ both in vitro and within the mitochondria of living cells. Additionally, these two novel near-infrared phosphorescent Ir(III) complexes demonstrate significant capabilities in producing ROS including singlet oxygen, ·O₂^- and ·OH, which renders them effective photosensitizers under visible light exposure for photodynamic therapy (PDT). This research offers a promising approach for detecting Hg²⁺ in vitro and in the mitochondrial microenvironment of living cells, which have some implications for the future development of pertinent transition metal complexes for mitochondria-targeted photodynamic therapy in cancer cells. Show less

Pediatric tumors such as neuroblastoma are characterized by a genome-wide ‘transcriptional burden’, surmising the involvement of multiple alterations of gene expression. Search for master regulators of transcription whose inactivation is lethal for tumor cells identified the non-POU domain-containing octamer-binding protein (NONO), a member of the Drosophila Behavior/Human Splicing family known for the ability to form complexes with macromolecules. NONO emerges as an essential mechanism in normal neurogenesis as well as in tumor biology. In particular, NONO interactions with RNAs, largely with long non-coding MYCN transcripts, have been attributed to the aggressiveness of neuroblastoma. Broadening its significance beyond MYCN regulation, NONO guards a subset of transcription factors that comprise a core regulatory circuit, a self-sustained loop that maintains transcription. As a component of protein–protein complexes, NONO has been implicated in the control of cell cycle progression, double-strand DNA repair, and, generally, in cell survival. Altogether, the pro-oncogenic roles of NONO justify the need for its inactivation as a therapeutic strategy. However, considering NONO as a therapeutic target, its druggability is a challenge. Recent advances in the inactivation of NONO and downstream signaling with small molecular weight compounds make promising the development of pharmacological antagonists of NONO pathway(s) for neuroblastoma treatment. Show less

AbstractTaxanes and platinum molecules, specifically paclitaxel and carboplatin, are widely used anticancer drugs that induce cell death and serve as first‐line chemotherapy for various cancer types. Despite the efficient effect of both drugs on cancer cell proliferation, many tumours have innate resistance against paclitaxel and carboplatin, which leads to inefficient treatment and poor survival rates. Haploid human embryonic stem cells (hESCs) are a novel and robust platform for genetic screening. To gain a comprehensive view of genes that affect or regulate paclitaxel and carboplatin resistance, genome‐wide loss‐of‐function screens in haploid hESCs were performed. Both paclitaxel and carboplatin screens have yielded selected plausible gene lists and pathways relevant to resistance prediction. The effects of mutations in selected genes on the resistance to the drugs were demonstrated. Based on the results, an algorithm that can predict resistance to paclitaxel or carboplatin was developed. Applying the algorithm to the DNA mutation profile of patients' tumours enabled the separation of sensitive versus resistant patients, thus, providing a prediction tool. As the anticancer drugs arsenal can offer alternatives in case of resistance to either paclitaxel or carboplatin, an early prediction can provide a significant advantage and should improve treatment. The algorithm assists this unmet need and helps predict whether a patient will respond to the treatment and may have an immediate clinically actionable application. Show less