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Colorectal cancer (CRC) remains a significant global health challenge, ranking third in incidence and second in mortality among cancers worldwide. This review addresses the complex landscape of CRC, focusing on incidence, mortality trends, preventive strategies, and the evolving therapeutic approaches, particularly highlighting the role of platinum-based drugs like oxaliplatin (OXP). It also underscores the increasing burden of CRC, with factors such as westernized diets, aging populations, and genetic predispositions contributing to its prevalence. Therapeutically, early detection greatly enhances survival rates, emphasizing the importance of regular colonoscopies and stool tests. For advanced CRC, chemotherapy remains pivotal, with OXP as a cornerstone treatment despite its associated chemotherapy-induced peripheral neurotoxicity (CIPN). The review explores innovative strategies to overcome challenges related to chemotherapy, such as drug resistance and side effects, highlighting recent developments in the field, such as Pt(IV) prodrugs and immunotherapeutic approaches to enhance efficacy while minimizing toxicity. Additionally, this manuscript examines experimental models for drug screening, emphasizing the role of murine models and advanced 3D in vitro systems in CRC research. Overall, the review advocates for a comprehensive approach, integrating prevention, early detection, and personalized treatments to alleviate the global burden of CRC. Show less

A fundamental biological mechanism, programmed cell death (PCD), is essential for tissue homeostasis, immunological control, and development. Its dysregulation is a characteristic of many diseases in multicellular organisms, including cancer, where unchecked proliferation is made possible by evading cell death. Therefore, one of the main tenets of contemporary anticancer therapies is the restoration or induction of PCD in cancer cells. One potential, least invasive method among these is photodynamic treatment (PDT). PDT uses light-activatable photosensitisers, which cause cancer cells to explode with reactive oxygen species (ROS) when exposed to light. These ROS harm important biomolecules, throw off the cellular redox equilibrium, and cause cells to die. PDT-induced cell death was previously believed to be mostly caused by autophagy, necrosis, or apoptosis. Recent research, however, has shown that it can trigger a wider range of unconventional cell death pathways. ROS can cause ferroptosis by oxidising membrane lipids, fragmenting DNA, and lowering intracellular glutathione (GSH) levels. Similarly, necroptosis or pyroptosis can result from severe oxidative stress activating death receptor signalling. Sometimes, in response, cells use survival strategies like autophagy, which can also lead to cell death. This review explores these new, unconventional methods of cell death and how PDT can be used to take advantage of them. Next-generation photosensitisers based on iridium (Ir), ruthenium (Ru), and rhenium (Re) complexes are given special attention because they provide deep tissue penetration, improved photostability, and adjustable ROS production. Their incorporation into PDT has revolutionary potential for improving cancer treatment precision and conquering therapeutic resistance. Show less

Despite the vast number of enzymatic kinetic measurements reported across decades of biochemical literature, the majority of relational enzyme kinetic data—linking amino acid sequence, substrate identity, kinetic parameters, and assay conditions—remains uncollected and inaccessible in structured form. This constitutes a significant portion of the “dark matter” of enzymology. Unlocking these hidden data through automated extraction offers an opportunity to expand enzyme dataset diversity and size, critical 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

Abstract RNA trafficking is crucial in almost every phase of plant development. Fibrillarin (FIB), a highly conserved nucleolar protein with methyltransferase (MTase) activity, functions in methylation and rRNA processing and facilitates the transport of several RNA viruses in plants. Previously, we demonstrated that bamboo mosaic virus satellite RNA (satBaMV) traffics autonomously and systemically in a helper virus-independent but FIB-dependent manner by forming a mobile ribonucleoprotein (RNP) complex comprising satBaMV, FIB, and satBaMV-encoded P20 movement protein. Here, we show that FIB methylates the arginine-rich motif (ARM) of P20 and relies on its MTase activity for the systemic movement of satBaMV. FIB MTase-defective mutants failed to complement long-distance satBaMV transport in FIBi plants, despite still binding to satBaMV in vivo. We also demonstrate that the ARM of P20 guides its nucleolar localization for FIB-mediated methylation. P20 methylation not only contributes to its plasmodesmata (PD) targeting but also triggers nucleocytoplasmic shuttling of FIB with P20 as the RNP complex to PD. A satBaMV mutant harboring a nonmethylated P20, but not a methylation-mimic P20, exhibited disrupted PD targeting and impaired P20-assisted satBaMV trafficking. Our findings provide mechanistic insights into how FIB-mediated P20 methylation positively regulates systemic trafficking of a subviral agent in plants. Show less

The preparation of a new series of Ir(III) tetrazolato complexes with the general formula [Ir(C^N)2(N^N)]0/+, where the ancillary ligand (N^N) is represented in turn by 2-pyridyltetrazolato (PTZ-), 2-pyrazinyltetrazolato (PYZ-) or 2-pyridyl 5-trifluoromethyl tetrazolato (PTZ-CF3-), is described herein. The design of the cyclometalated (C^N) ligands, namely 2-phenylisonicotinonitrile (ppyCN) and 2-(2,4-difluorophenyl)isonicotinonitrile (F2ppy-CN), features the well-known ppy- or F2ppy core, with the introduction of one electron-withdrawing cyano (-CN) group at the para position of the pyridyl ring. The photophysical and electrochemical properties of the new Ir(III) cyclometalated complexes have been investigated and the resulting data suggest how the (C^N) ligands significantly rule the luminescence behavior of the new complexes. Further blue or red shifting of the emission profiles of the neutral complexes was observed upon their conversion into cationic species through the regioselective addition of a methyl moiety to the coordinated tetrazolato ring. Lastly, neutral [Ir(F2ppy-CN)2(PTZ)] was used as an emissive phosphor for the fabrication of an OLED-type device. 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

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

Structured RNAs are increasingly explored as novel pharmacological targets for a range of diseases. Therefore, evaluating methods for RNA-focused hit discovery is crucial. Biolayer Interferometry (BLI), a label-free technique that detects biomolecular interactions by measuring changes in white light interference near the sensor surface, offers high throughput and multiplexing capabilities. While BLI has been widely adopted for protein-targeted screening, its application in RNA-targeted drug discovery remains largely unexplored. In this study, we demonstrate the effective use of BLI to investigate RNA–small molecule interactions using three different riboswitches, which are potential targets for novel antibiotics. Furthermore, we describe the successful use of BLI to identify fragment binders of these RNA targets. We combined the BLI experiments with ligand-based NMR as an orthogonal validation method and were able to identify seven competitive fragment binders of the flavin mononucleotide (FMN) riboswitch, each featuring scaffolds distinct from the previously known ligands. Show less

Colorectal cancer (CRC) remains a significant oncological challenge, being among the foremost contributors to cancer-related mortality worldwide. This review summarizes our current knowledge regarding how metabolic reprogramming, specifically the Warburg effect, contributes to CRC pathobiology and explores its therapeutic relevance. Metabolic reprogramming in CRC is characterized by a shift from oxidative phosphorylation to glycolysis, termed the Warburg effect. Driven by the tumor microenvironment (TME), this adaptation enhances cancer cell proliferation through accelerated ATP generation, biosynthesis support, and redox balance. Key glycolytic enzymes, namely hexokinase, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase are now prioritized as therapeutic targets in CRC treatment strategies. Diagnostic modalities utilizing CRC’s altered metabolism such as 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT) and metabolomic analysis of circulating metabolites, improved early detection through enhanced sensitivity and specificity. These approaches reveal CRC’s distinct metabolic signatures, enabling precise disease stratification and management. Therapeutic strategies targeting the EMP pathway show preclinical efficacy in overcoming CRC-associated chemoresistance and radioresistance. Modulation of EMP-regulating pathways (AKT, AMPK, mTOR) provides additional therapeutic opportunities. However, CRC’s metabolic heterogeneity demands multi-targeted approaches. The development of targeted therapies must consider the potential off-target effects on normal tissues that rely on EMP, necessitating a careful balance between therapeutic efficacy and safety. In summary, this review underscores the complexity of metabolic reprogramming in CRC and the need for a nuanced approach to target these pathways effectively. Subsequent investigations should prioritize defining tumor-selective metabolic vulnerabilities and engineering multi-pathway interventions that spare normal tissues, ultimately advancing therapeutic precision in CRC management. Show less

Water is arguably one of the most important chemicals essential for the functioning of biological molecules. In the context of DNA, it plays a crucial role in stabilizing and modulating its structure and function. The discovery of water-bound motifs in crystal structures has greatly improved our understanding of the interactions between structured water molecules and DNA. In this manuscript, we review the role of water in mediating biologically relevant DNA structures, in particular those arising from epigenetic modifications and higher-order structures such as G-quadruplexes and i-motifs. We also examine water-mediated interactions between DNA and various small molecules, including groove binders and intercalators, and emphasize their importance for DNA function and therapeutic development. Finally, we discuss recent advances in tools and techniques for predicting water interactions in nucleic acid structures. By offering a fresh perspective on the role of water, this review underscores its importance as a molecular modulator of DNA structure and function. Show less

A ‘turn-on’ iridium( iii ) complex probe (Ir-CHO) with favorable photophysical properties was developed for the selective and rapid detection of SO 2 . Its utility was validated in living cells and tumor-bearing mice. TLDR: The results suggest that this new probe Ir-CHO could monitor SO2 derivatives in real time within tumor microenvironment research, highlighting its promising diagnostic potential for future clinical and biomedical applications. Show less

Conformer generation is crucial for computational chemistry tasks such as structure-based modeling and property prediction. Although reliable methods exist for organic molecules, coordination complexes remain challenging due to their diverse coordination geometries, ligand types, and stereochemistry. Current tools often lack the flexibility and reliability required for these systems. Here, we introduce MetalloGen, a novel algorithm designed for the automated generation of 3D conformers of mononuclear coordination complexes. MetalloGen accepts either SMILES strings or molecular graph representations as input and enables the generation of reliable conformers, including those with multiple polyhapto ligands, which are typically inaccessible to conventional conformer generators. To rigorously assess MetalloGen's performance, we benchmarked it on three distinct data sets: a curated collection of experimentally determined structures from the Cambridge Structural Database, the MOR41 benchmark set encompassing a wide range of organometallic reactions and complex ligand environments, and three catalytic reactions. Across all test sets, MetalloGen consistently reproduced appropriate geometries with high fidelity and demonstrated robust stereochemical control, even for challenging cases involving multiple polyhapto ligands. The versatility and reliability of MetalloGen make it a valuable tool for more accurate and efficient computational investigations in inorganic and organometallic chemistry. Show less

We hypothesize that predictable variations in environmental conditions caused by night/day cycles created opportunities and hazards that initiated information dynamics central to life’s origin. Increased daytime temperatures accelerated key chemical reactions but also caused the separation of double-stranded polynucleotides, leading to hydrolysis, particularly of single-stranded RNA. Daytime solar UV radiation promoted the synthesis of organic molecules but caused broad damage to protocell macromolecules. We hypothesize that inter-related simultaneous adaptations to these hazards produced molecular dynamics necessary to store and use information. Self-replicating RNA heritably reduced the hydrolysis of single strands after separation during warmer daytime periods by promoting sequences that formed hairpin loops, generating precursors to transfer RNA (tRNA), and initiating tRNA-directed evolutionary dynamics. Protocell survival during daytime promoted sequences in self-replicating RNA within protocells that formed RNA–peptide hybrids capable of scavenging UV-induced free radicals or catalyzing melanin synthesis from tyrosine. The RNA–peptide hybrids are precursors to ribosomes and the triplet codes for RNA-directed protein synthesis. The protective effects of melanin production persist as melanosomes are found throughout the tree of life. Similarly, adaptations mitigating UV damage led to the replacement of Na+ by K+ as the dominant mobile cytoplasmic cation to promote diel vertical migration and selected for homochirality. We conclude that information dynamics emerged in early life through adaptations to predictably fluctuating opportunities and hazards during night/day cycles, and its legacy remains observable in extant life. Show less

Abstract The first examples of Ru(II) η 6 ‐arene (benzene and p ‐cymene) complexes containing a bidentate triazolylidene‐triazolide ligand have been prepared and fully characterized. Their antiproliferative effect has been investigated against tumour cells A2780 (ovarian carcinoma), HCT116 (colorectal carcinoma), and HCT116dox (colorectal carcinoma resistant to doxorubicin), and in human dermal fibroblasts. The Ru complex bearing the p ‐cymene arene group exhibited a stronger antiproliferative effect across all tested cell lines, while the benzene‐containing complex displayed higher selectivity toward tumor cells. Both complexes induced apoptosis, likely through ROS production (in the benzene complex), and inhibited tumorigenic processes, including cell migration and angiogenesis. In zebrafish models, they showed strong selectivity for cancer cells with minimal toxicity to healthy cells, effectively reducing the proliferation of HCT116 colorectal cancer cells. This study provides the first in vivo evidence of the anticancer potential of Ru triazolylidenes in zebrafish models. 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

ABSTRACTThe nucleolus, a prominent membrane‐less nuclear compartment, is organized around ribosomal RNA (rRNA) gene (rDNA) clusters, known as nucleolar organizing regions (NORs), located on the short arms of acrocentric chromosomes. It serves as the primary site for ribosome biogenesis, an energy‐intensive process crucial for cell growth and proliferation. This involves RNA polymerase I (Pol I)‐mediated transcription of 47S precursor rRNA (pre‐rRNA), pre‐rRNA processing, and ribosomal subunit assembly, reflected in its tripartite structure maintained by liquid–liquid phase separation. Recent evidence indicates that only about 30% of nucleolar proteins are exclusively involved in ribosome production. The remaining proteome participates in diverse cellular functions, establishing the nucleolus as a multifunctional organelle. It functions as a critical stress sensor and signaling hub, responding to various intracellular insults such as nutrient starvation, DNA damage, and viral infection. Many chemotherapeutic agents also induce the response called nucleolar stress via disruption of the nucleolar structure or function, potentially leading to rDNA instability. Nucleolar stress frequently leads to dynamic transition of nucleolar proteins, inducing nucleolar reorganization. Of these, the stress induced by transcriptional changes leads to the unique nucleolar structures termed nucleolar caps and nucleolar necklaces. In this review, we summarize the recent findings about the molecular mechanism of nucleolar changes upon stresses and discuss the possible relationship between rDNA instability and cancer. Show less

We introduce ruthenosomes, a fusion of liposomal and reactive oxygen species (ROS)-generating properties meticulously engineered as potent ferroptosis inducers (FINs), marking a significant advancement in metallodrug design for cancer therapy. Formed through the self-assembly of oleate-conjugated ruthenium complexes, these ruthenosomes exhibit exceptional cellular uptake, selectively accumulating in mitochondria and causing substantial disruption. This targeted mitochondrial damage significantly elevates ROS levels, triggering autophagy and selectively activating ferritinophagy. Together, these processes sensitize cancer cells to ferroptosis. In vivo, ruthenosomes effectively suppress colorectal tumor growth, underscoring their therapeutic potential. Our study pioneers a design strategy that transforms ruthenium complexes into liposome-like structures capable of inducing ferroptosis independent of light activation. By leveraging ruthenosomes as multifunctional nanocarriers, this research offers a versatile and powerful platform for ROS-mediated, ferroptosis-driven cancer cell eradication. Show less

N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic mRNA and has emerged as a pivotal regulator of gene expression at the post-transcriptional level. In the tumor immune microenvironment, tumor-associated macrophages (TAMs) represent a highly plastic and heterogeneous population that profoundly influences cancer progression, immune evasion, and therapeutic response. Recent studies have uncovered that m6A modification, mediated by dynamic “writers,” “erasers,” and “readers,” exerts critical regulatory effects on TAM differentiation, polarization, and functional reprogramming. By modulating the stability, translation, and decay of transcripts involved in inflammatory signaling, metabolic adaptation, and immune checkpoints, m6A shapes the balance between tumor-promoting (M2-like) and tumor-suppressive (M1-like) macrophage phenotypes. Moreover, dysregulation of m6A machinery in TAMs has been linked to the suppression of anti-tumor immunity and resistance to immunotherapy, highlighting its translational potential as a therapeutic target. This review summarizes current advances in understanding the roles and mechanisms of m6A modification in TAM biology, discusses its implications in tumor immunity, and outlines the challenges and opportunities of targeting the m6A–TAM axis for cancer treatment. Show less