👤 Fang F

Geological structures known as alkaline hydrothermal vents (AHVs) likely displayed dynamic energy characteristics analogous to cellular chemiosmosis and contained iron-oxyhydroxide green rusts in the early Earth. Under specific conditions, those minerals could have acted as non-enzymatic catalysts in the development of early bioenergetic chemiosmotic energy systems while being integrated into the membrane of AHV-produced organic vesicles. Here, we show that the simultaneous addition of two probable AHV components, namely nickel and amino acids, impacts green rust's physico-chemical properties, especially those required for its incorporation in lipid vesicle's membranes, such as decreasing the mineral size to the nanometer scale and increasing its hydrophobicity. These results suggest that such hydrophobic nano green rusts could fit into lipid vesicle membranes and could have functioned as a primitive, inorganic precursor to modern chemiosmotic metalloenzymes, facilitating both electron and proton transport in early life-like systems. Show less

Drug-drug interactions (DDI) are an important cause of adverse drug reactions (ADRs). Could large language models (LLMs) serve as valuable tools for pharmacovigilance specialists in detecting DDIs that lead to ADR notifications? Show less

Ferroptosis is a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, which plays a critical role in the pathogenesis of various diseases, including ischemic tissue injury, infectious diseases, neurodegenerative disorders, and cancer. The regulatory mechanisms underlying ferroptosis involve a complex interplay of multiple subcellular organelles, orchestrating iron homeostasis, lipid metabolism, and the generation of reactive oxygen species (ROS) that drive peroxidation processes, ultimately leading to membrane damage and cell death. Numerous antioxidant systems play pivotal roles in regulating and preventing ferroptosis, among which the recently identified mitochondrial inner membrane enzyme dihydroorotate dehydrogenase (DHODH) represents a novel therapeutic target for ferroptosis intervention. This systematic review comprehensively elucidates several key cellular defense mechanisms against ferroptosis that counteract ROS-driven peroxidation and operate through distinct subcellular localizations. We particularly focus on delineating the molecular mechanisms by which DHODH regulates ferroptosis, with special emphasis on its role in suppressing mitochondrial lipid peroxidation. Furthermore, we systematically evaluate the therapeutic potential of DHODH inhibitors in oncology, virology, and immune-inflammatory disorders. By integrating ferroptosis biology with DHODH-mediated cytoprotective networks, this review aims to provide mechanistic insights and novel therapeutic strategies for cancer and oxidative stress-related disorders. Show less

Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation. It plays a crucial role in various pathological conditions, including neurodegenerative diseases, cancer, ischemia-reperfusion injury, and organ failure. This review systematically explores the key mechanisms underlying ferroptosis, including polyunsaturated fatty acid-containing phospholipid (PUFA-PL) peroxidation, iron metabolism, and mitochondrial dysfunction. Additionally, we summarize major endogenous ferroptosis defense systems, including the SLC7A11-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis, the ferroptosis suppressor protein 1 (FSP1)-ubiquinol (CoQH₂) system, the mitochondrial dihydroorotate dehydrogenase (DHODH)-CoQH₂ pathway, and the guanosine triphosphate cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4) pathway, which act as critical brakes on ferroptosis. Furthermore, we discuss various small-molecule inhibitors targeting ferroptosis, categorized by their mechanisms of action, including iron chelators, lipid peroxidation inhibitors, antioxidants, and regulatory pathway modulators. Recent advances in pharmacological strategies and their potential therapeutic applications are also highlighted. Show less

Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment. 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

The aim of the UniProt Knowledgebase (UniProtKB; https://www.uniprot.org/) is to provide users with a comprehensive, high-quality and freely accessible set of protein sequences annotated with functional information. In this publication, we describe ongoing changes to our production pipeline to limit the sequences available in UniProtKB to high-quality, non-redundant reference proteomes. We continue to manually curate the scientific literature to add the latest functional data and use machine learning techniques. We also encourage community curation to ensure key publications are not missed. We provide an update on the automatic annotation methods used by UniProtKB to predict information for unreviewed entries describing unstudied proteins. Finally, updates to the UniProt website are described, including a new tab linking protein to genomic information. In recognition of its value to the scientific community, the UniProt database has been awarded Global Core Biodata Resource status. Show less

Title: Small upconversion-ruthenium nanohybrids for cancer theranostics. Abstract: Photoresponsive drug delivery systems have great potential for improved cancer therapy. However, most of the currently available drug-delivery nanosystems are relatively large and require light excitation with low tissue penetration. Here, we designed a near infrared responsive drug delivery system by loading [Ru(terpyridine)(dipyridophenazine)(H2O)]2+ (Ru(tpy)DPPZ) in azobenzene-modified mesoporous silica coated NaGdF4:Nd0.01/Yb0.2/Tm0.01 upconversion nanoparticles (azo-mSiO2-UCNPs). Upon 808 nm excitation, the generated ultraviolet and blue upconversion luminescence induced a reversible cis-trans isomerization of azobenzene for on-demand release of Ru(tpy)DPPZ. Imaging of both the UCNPs and Ru(tpy)DPPZ revealed targeted drug delivery to the nucleus of MCF-7 breast cancer cells, inducing DNA damage and concomitant cell destruction. Considering that cell nuclei are the core of cellular transcription and the main site of action for multiple chemotherapeutic drugs, our NIR-excitable and small (10 nm diameter) nanohybrids can potentially become highly versatile tools for targeted cancer theranostics. Show less

Ruthenium-based metallodrugs have garnered attention as a promising alternative for anticancer therapy, aiming to overcome chemoresistance and severe side effects linked to platinum-based drugs. However, ruthenium complexes tested in clinical trials to date have yielded unsatisfactory results. This study synthesized a positively charged ruthenium complex (Ru-2) that effectively penetrated cancer cells and exhibited superior cytotoxicity to cisplatin in vitro against cancer cell lines and organoids. Ru-2 selectively targeted mitochondria, disrupting their function by depolarizing mitochondrial membrane potential, elevating reactive oxygen species production, and impairing both oxidative phosphorylation and the tricarboxylic acid cycle. Furthermore, Ru-2 triggered endoplasmic reticulum (ER) stress and apoptosis. Integrative transcriptomic and proteomic analyses, performed using RNA sequencing and mass spectrometry, identified key molecular changes in cancer cells treated with Ru-2. For enhanced in vivo application, we developed a transferrin-based nanomedicine formulation, TF/Ru-2, incorporating Ru-2 into transferrin. In vivo studies demonstrated that both Ru-2 and TF/Ru-2 exhibited superior antitumor efficacy and improved biosafety compared to cisplatin. This study presents a novel ruthenium complex and a transferrin-based drug delivery platform with significant potential for future cancer therapies. Show less

Cancer resistance to chemotherapeutic agents such as cisplatin presents a significant challenge, leading to treatment failure and poor outcomes. Novel metal-based compounds offer a promising strategy to overcome drug resistance and to enhance efficacy. Four Ru(II) complexes with fenamic acid derivatives were synthesized and characterized: [Ru(L)(bipy)(dppp)]PF₆, where L represents fenamic acid (HFen, complex 1), mefenamic acid (HMFen, complex 2), tolfenamic acid (HTFen, complex 3), and flufenamic acid (HFFen, complex 4). Their composition was supported by molar conductivity, elemental analysis, Fourier transform infrared spectroscopy, ultraviolet-visible spectroscopy, mass spectrometry, and ³¹P{¹H}, ¹H, and ¹³C nuclear magnetic resonance, with the crystal structure of complex 1 confirmed via X-ray diffraction. Complexes 1-4 exhibited notable cytotoxicity against tested cell lines, particularly A2780 and A2780cisR (cisplatin-resistant ovarian tumors), compared to MDA-MB-231 (breast) and A549 (lung) lines. Mechanistic studies revealed weak DNA interactions through minor grooves or electrostatic binding. Cellular uptake assays showed effective internalization of complexes 1 (3.6%) and 2 (4.5%), correlating with potent IC₅₀ values. These complexes also altered cell morphology, reduced cell density, and inhibited colony formation in the A2780 cells. Staining assays indicated induced cell death and organelle damage, highlighting their potential as promising antitumor agents. Show less

The six mononuclear Schiff's base Ru(III) complexes viz., [Ru(BZP)(LA)₂].2NO₃ (MRA), [Ru(BZP)(LB)₂].2NO₃ (MRB), [Ru(BZP))(LC)₂].2NO₃ (MRC), [Ru(BZP))(LD)₂].2NO₃ (MRD), [Ru(BZP)(LE)₂].2NO₃ (MRE) and [Ru(BZP)(LF)₂].2NO₃ (MRF), were synthesized using of (BZP=2,6-bis(2-benzimidazolyl)pyridine and p-sub-benzylthiosemicarbazones (BTS) [(Sub=4-NO₂ (LA), 4-N(CH₃)₂ (LB), 4-Cl (LC), 4-OCH₃ (LD), 4-OCH₂Ph (LE), and 4-OH (LF)] as an ancillary ligands. The thiosemicarbazones ligands (LA-LF) were obtained by the condensation of p-substituted benzaldehyde and thiosemicarbazide. These complexes were characterized by elemental analysis, IR, ESR, ESI-MS, electronic absorption spectroscopy. The geometry was optimized by theoretical calculation using DFT and structure reveals that MRA-MRF adopt octahedral geometry. Further, the complexes were examined for anti-cancer against Leukemia cancer cell line K562 and shown significant responses to these cells. Moreover, DNA binding studies were conducted with all complexes MRA-MRF and the binding constant (K_b) were found i.e., 1.10×10⁴, 1.54×10⁴, 2.87×10⁴, 1.67×10⁴, 1.98×10⁴ and 1.59×10⁴, respectively. It was found that DNA binds in intercalation mode which is also validated by the docking studies. 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

While molecular isomers exhibit nearly identical compositions, their spatial arrangement often dictates distinct physicochemical properties. We present a regioisomer engineering strategy to construct two iridium(III) complexes (Ir1 and Ir2) through precise positioning of triphenylamine electron donors relative to the metal chelation core. Compared to Ir1, Ir2 features strategically displaced donors that create a contracted bandgap, reduced oxidation potential, and amplified spin-orbit coupling (SOC). These electronic modifications synergistically enable Ir2 to achieve superior type I photodynamic activity and thus generate O₂^•- and •OH radicals after 633 nm irradiation even under hypoxic conditions. The sustained reactive oxygen species (ROS) production induces potent immunogenic cell death (ICD), ultimately stimulating dendritic cell maturation and antitumor immunity. This regioisomeric design paradigm establishes a molecular blueprint for oxygen-tolerant photosensitizers, addressing the critical challenge of hypoxia in photoimmunotherapy applications. Show less

Title: Monomer Versus Dimer of Cationic Ir(III) Complexes for Photodynamic Therapy by Two-Photon Activation: A Comparative Study. Abstract: Iridium(III) complexes have been recognized as promising candidates for two-photon sensitized photodynamic therapy (PDT). In this context, we report on the study of two complexes: a monomer (IrL1) and a dimer (Ir2L2). Both complexes possess 2-phenylpyridine cyclometallating ligands and a pyridylbenzimidazole derivative as an ancillary ligand. In the dimer, the two Ir(III) centers are connected by a non-conjugated bridged bis(pyridylbenzimidazole). We compare the photophysical properties of these complexes. Both display phosphorescent emission in the orange-red part of the visible spectrum, with emissions centered at 610 nm for IrL1 and 625 nm for Ir2L2, both exhibiting quantum yields of ∼24%. However, Ir2L2 proves to be much brighter than the monomer, making the dimer four times brighter than IrL1. This trend is consistent under two-photon excitation (TPE), and the singlet oxygen generation quantum yields, with the dimer displaying a figure of merit (σTPA × ΦΔ) of 40, compared to only 5 for the monomer. Both complexes generate intracellular ROS and exhibit strong phototoxicity upon blue light activation (λ = 420 nm), achieving submicromolar IC50 values in HT29 and A549 cell lines after 24 h of incubation. Moreover, with TPE (λ = 800 nm), both complexes also generate intracellular ROS and induce cancer cell death. Show less

Hydrogen sulfide (H2S) played a pivotal role in the early evolution of life on Earth before the predominance of atmospheric oxygen. The legacy of a persistent role for H2S in life's processes recently emerged through its discovery in modern biochemistry as an endogenous cellular signalling modulator involved in numerous biological processes. One major mechanism through which H2S signals is protein cysteine persulfidation, an oxidative post-translational modification. In recent years, chemoproteomic technologies have been developed to allow the global scanning of protein persulfidation targets in mammalian cells and tissues, providing a powerful tool to elucidate the broader impact of altered H2S in organismal physiological health and human disease states. While hundreds of proteins were confirmed to be persulfidated by global persulfidome methodologies, the targeting of specific proteins of interest and the investigation of further mechanistic studies are still underdeveloped due to a lack of stringent specificity of the methods and the inherent instability of persulfides. This review provides an overview of the processes of endogenous H2S production, oxidation, and signalling and highlights the application and limitations of current persulfidation labelling approaches for investigation of this important evolutionarily conserved biological switch for protein function. Show less

Efforts to identify anti-cancer therapeutics and understand tumor-immune interactions are built with in vitro models that do not match the microenvironmental characteristics of human tissues. Using in vitro models which mimic the physical properties of healthy or cancerous tissues and a physiologically relevant culture medium, we demonstrate that the chemical and physical properties of the microenvironment regulate the composition and topology of the glycocalyx. Remarkably, we find that cancer and age-related changes in the physical properties of the microenvironment are sufficient to adjust immune surveillance via the topology of the glycocalyx, a previously unknown phenomenon observable only with a physiologically relevant culture medium. Show less

In the era of high throughput sequencing, special software is required for the clinical evaluation of genetic variants. We developed REEV (Review, Evaluate and Explain Variants), a user-friendly platform for clinicians and researchers in the field of rare disease genetics. Supporting data was aggregated from public data sources. We compared REEV with seven other tools for clinical variant evaluation. REEV (semi-)automatically fills individual ACMG criteria facilitating variant interpretation. REEV can store disease and phenotype data related to a case to use these for phenotype similarity measures. Users can create public permanent links for individual variants that can be saved as browser bookmarks and shared. REEV may help in the fast diagnostic assessment of genetic variants in a clinical as well as in a research context. REEV (https://reev.bihealth.org/) is free and open to all users and there is no login requirement. Show less

Background As desmoid-type fibromatosis (DF) exhibits a high recurrence rate after surgery, initial active surveillance followed by medical therapy is the mainstay of the treatment. However, there are few effective drugs with acceptable side effects. Methodology Among drugs that have been used for a long period and possess a known safety profile, auranofin was observed to be effective in suppressing DF using the drug repositioning method in our laboratory. This clinical study has been designed to examine the efficacy and safety of auranofin, an approved anti-rheumatic drug, in patients with progressive DF. Results This study is conducted as a single-center, single-arm, open-label study. Auranofin 3 mg tablets will be administered twice daily to DF patients with progressive disease. The primary endpoint is progression-free survival at 26 weeks after starting treatment. Secondary endpoints include response rate, T2-weighted MRI evaluation, pain intensity, quality of life (QOL), and safety assessment. Conclusions This is the first clinical trial of auranofin in patients with aggressive DF. The study will allow an in-depth understanding of the efficacy of auranofin for response rate as well as for changes in MRI findings, pain, and QOL in patients with aggressive DF. Show less

Title: Mitochondria-targeted ruthenium(II) complexes for photodynamic therapy and GSH detection in living cells. Abstract: Photodynamic therapy is an emerging tumor therapy that kills tumor cells by activating reactive oxygen species (ROS) produced by photosensitizers. Mitochondria, as an important organelle, are the main generator of cellular ROS. Therefore, the development of photosensitizers capable of targeting mitochondria could significantly enhance the efficacy of photodynamic therapy. In this study, two novel ruthenium(II) complexes, Ru-1 and Ru-2, were designed and synthesized, both of which were functionalized with α,β-unsaturated ketones for sensing of glutathione (GSH). The crystal structures of the two complexes were determined and they exhibited good recognition of GSH by off-on luminescence signals. The complex Ru-2 containing aromatic naphthalene can enter the cells and react with GSH to generate a strong luminescence signal that can be used to monitor intracellular GSH levels through imaging. Ru-2 also has an excellent mitochondrial localization ability with a Pearson's coefficient of 0.95, which demonstrates that it can efficiently target the mitochondria of tumor cells to enhance the effectiveness of photodynamic therapy as a photosensitizer. Show less

Dysregulation of Fibroblast Growth Factor Receptors (FGFRs) signaling has been associated with breast cancer, yet employing FGFR-targeted delivery systems to improve the efficacy of cytotoxic agents is still sparsely exploited. Herein, we report four new bi-functional ruthenium-peptide conjugates (RuPCs) with FGFR-targeting and pH-dependent releasing abilities, envisioning the selective delivery of cytotoxic Ru complexes to FGFR(+)-breast cancer cells, and controlled activation at the acidic tumoral microenvironment. The antiproliferative potential of the RuPCs and free Ru complexes was evaluated in four breast cancer cell lines with different FGFR expression levels (SKBR-3, MDA-MB-134-VI, MCF-7, and MDA-MB-231) and in human dermal fibroblasts (HDF), at pH 6.8 and pH 7.4 aimed at mimicking the tumor microenvironment and normal tissues/bloodstream pHs, respectively. The RuPCs showed higher cytotoxicity in cells with higher level of FGFR expression at acidic pH. Additionally, RuPCs showed up to 6-fold higher activity in the FGFR(+) breast cancer lines compared to the normal cell line. The release profile of Ru complexes from RuPCs corroborates the antiproliferative effects observed. Remarkably, the cytotoxicity and releasing ability of RuPCs were shown to be strongly dependent on the conjugation of the peptide position in the Ru complex. Complementary molecular dynamic simulations and computational calculations were performed to help interpret these findings at the molecular level. In summary, we identified a lead bi-functional RuPC that holds strong potential as a FGFR-targeted chemotherapeutic agent. Show less

The therapeutic approach to many solid tumors, including non-small cell lung cancer (NSCLC), is mainly based on the use of platinum-containing anticancer agents and is often characterized by acquired or intrinsic resistance to the drug. Therefore, the search for safer and more effective drugs is still an open challenge. Two organometallic ruthenium(II)-cyclopentadienyl compounds [Ru(η⁵-C₅H₄CHO)(Me₂bipy)(PPh₃)]⁺ (RT150) and [Ru(η⁵-C₅H₄CH₂OH)(Me₂bipy)(PPh₃)][CF₃SO₃] (RT151) were tested against a panel of cisplatin-resistant NSCLC cell lines and xenografts. They were more effective than cisplatin in inducing oxidative stress and DNA damage, affecting the cell cycle and causing apoptosis. Importantly, they were found to be inhibitors of drug efflux transporters. Due to this property, the compounds significantly increased the retention and cytotoxicity of cisplatin within NSCLC cells. Notably, they did not display high toxicity in vitro against non-transformed cells (red blood cells, fibroblasts, bronchial epithelial cells, cardiomyocytes, and endothelial cells). Both compounds induced vasorelaxation and reduced endothelial cell migration, suggesting potential anti-angiogenic properties. RT151 confirmed its efficacy against NSCLC xenografts resistant to cisplatin. Either alone or combined with low doses of cisplatin, RT151 showed a good biodistribution profile in the liver, kidney, spleen, lung, and tumor. Hematochemical analysis and post-mortem organ pathology confirmed the safety of the compound in vivo, also when combined with cisplatin. To sum up, we have confirmed the effectiveness of a novel class of drugs against cisplatin-resistant NSCLC. Additionally, the compounds have a good biocompatibility and safety profile. Show less

Using photodynamic therapy (PDT) to trigger nonconventional cell death pathways has provided a new scheme for highly efficient and non-side effects to drug-resistant cancer therapies. Nonetheless, the unclear targets of available photosensitizers leave the manner of PDT-induced tumor cell death relatively unpredictable. Herein, we developed a novel Ru(II)-based photosensitizer, Ru-Poma. Possessing the E3 ubiquitin ligase CRBN-targeting moiety and high singlet oxygen yield of 0.96, Ru-Poma was demonstrated to specifically photodegrade endogenous CRBN, increase lipid peroxide, downregulate GPX4 and GAPDH expression, and consequently induce ferroptosis in cisplatin-resistant cancerous cells. Furthermore, with the deep penetration of two-photon excitation, Ru-Poma achieved drug-resistant circumvention in a 3D tumor cell model. Thus, we describe the first sample of the CRBN-targeting Ru(II) complex active in PDT. Show less

Title: Insights into the anticancer photodynamic activity of Ir(III) and Ru(II) polypyridyl complexes bearing β-carboline ligands. Abstract: Ir(III) and Ru(II) polypyridyl complexes are promising photosensitizers (PSs) for photodynamic therapy (PDT) due to their outstanding photophysical properties. Herein, one series of cyclometallated Ir(III) complexes and two series of Ru(II) polypyridyl derivatives bearing three different thiazolyl-β-carboline N^N' ligands have been synthesized, aiming to evaluate the impact of the different metal fragments ([Ir(C^N)2]+ or [Ru(N^N)2]2+) and N^N' ligands on the photophysical and biological properties. All the compounds exhibit remarkable photostability under blue-light irradiation and are emissive (605 < λem < 720 nm), with the Ru(II) derivatives displaying higher photoluminescence quantum yields and longer excited state lifetimes. The Ir PSs display pKa values between 5.9 and 7.9, whereas their Ru counterparts are less acidic (pKa > 9.3). The presence of the deprotonated form in the Ir-PSs favours the generation of reactive oxygen species (ROS) since, according to theoretical calculations, it features a low-lying ligand-centered triplet excited state (T1 = 3LC) with a long lifetime. All compounds have demonstrated anticancer activity. Ir(III) complexes 1-3 exhibit the highest cytotoxicity in dark conditions, comparable to cisplatin. Their activity is notably enhanced by blue-light irradiation, resulting in nanomolar IC50 values and phototoxicity indexes (PIs) between 70 and 201 in different cancer cell lines. The Ir(III) PSs are also activated by green (with PI between 16 and 19.2) and red light in the case of complex 3 (PI = 8.5). Their antitumor efficacy is confirmed by clonogenic assays and using spheroid models. The Ir(III) complexes rapidly enter cells, accumulating in mitochondria and lysosomes. Upon photoactivation, they generate ROS, leading to mitochondrial dysfunction and lysosomal damage and ultimately cell apoptosis. Additionally, they inhibit cancer cell migration, a crucial step in metastasis. In contrast, Ru(II) complex 6 exhibits moderate mitochondrial activity. Overall, Ir(III) complexes 1-3 show potential for selective light-controlled cancer treatment, providing an alternative mechanism to chemotherapy and the ability to inhibit lethal cancer cell dissemination. Show less

Title: A Ru(II) complex-based COX-2 targeting type I photosensitizer evokes ferroptosis and apoptosis. Abstract: Photodynamic therapy (PDT) often faces challenges such as oxygen dependence and limited tumour specificity. We report a tumour-targeting photosensitizer (PS), RuCXB, which enhances uptake by cancer cells by targeting overexpressed cyclooxygenase-2 enzyme in tumours. RuCXB also reduces oxygen dependence via a type I PDT mechanism and achieves a strong therapeutic effect through the synergistic induction of ferroptosis and apoptosis. This work presents a reliable strategy for developing potent PSs with enhanced PDT efficacy, tumour selectivity, and diminished oxygen dependence. Show less

Identification of intracellular targets of anticancer drug candidates provides key information on their mechanism of action. Exploiting the ability of the anticancer (C∧N)-chelated half-sandwich iridium(III) complexes to covalently bind proteins, click chemistry with a bioorthogonal azido probe was used to localize a phenyloxazoline-chelated iridium complex within cells and profile its interactome at the proteome-wide scale. Proteins involved in protein folding and actin cytoskeleton regulation were identified as high-affinity targets. Upon iridium complex treatment, the folding activity of Heat Shock Protein HSP90 was inhibited in vitro and major cytoskeleton disorganization was observed. A wide array of imaging and biochemical methods validated selected targets and provided a multiscale overview of the effects of this complex on live human cells. We demonstrate that it behaves as a dual agent, inducing both electrophilic and oxidative stresses in cells that account for its cytotoxicity. The proposed methodological workflow can open innovative avenues in metallodrug discovery. Show less

In this paper, three new iridium(III) complexes: [Ir(piq)₂(DFIPP)]PF₆ (piq = deprotonated 1-phenylisoquinoline, DFIPP = 3,4-difluoro-2-(1H-imidazo[4,5-f][1,10]phenenthrolin-2-yl)phenol, 3a), [Ir(bzq)₂(DFIPP)]PF₆ (bzq = deprotonated benzo[h]quinoline, 3b), and [Ir(ppy)₂(DFIPP)]PF₆ (ppy = deprotonated 1-phenylpyridine, 3c), were synthesized and characterized. The complexes were found to be nontoxic to tumor cells via 3-(4,5-dimethylthiazole-2-yl)-diphenyltetrazolium bromide (MTT) assay. Surprisingly, its liposome-entrapped complexes 3alip, 3blip, and 3clip on B16 cells showed strong cytotoxicity (IC₅₀ = 13.6 ± 2.8, 9.6 ± 1.1, and 18.9 ± 2.1 μM). Entry of 3alip, 3blip, and 3clip into B16 cells decreases mitochondrial membrane potential, regulates Bcl-2 family proteins, releases cytochrome c, triggers caspase family cascade reaction, and induces apoptosis. In addition, we also found that 3alip, 3blip, and 3clip triggered ferroptosis and autophagy. In vivo studies demonstrated that 3blip inhibited melanoma growth in C57 mice with a high inhibitory rate of 83.95%, and no organic damage was found in C57 mice. Show less

Title: Synthesis and mitochondria-localized iridium (III) complexes induce cell death through pyroptosis and ferroptosis pathways. Abstract: This paper introduces a new ligand, 4,6-dichloro-5-(1H-imidazo [4,5-f]phenanthroline-2-yl)pyrimidin-2-amine (DPPA), and its corresponding new iridium(III) complexes: [Ir(ppy)2(DPPA)](PF6) (2a) (where ppy represents deprotonated 2-phenylpyridine), [Ir(bzq)2(DPPA)](PF6) (2b) (with bzq indicating deprotonated benzo[h]quinoline), and [Ir(piq)2(DPPA)](PF6) (2c) (piq denoting deprotonated 1-phenylisoquinoline). The cytotoxic effects of both DPPA and 2a, 2b, and 2c were evaluated against human lung carcinoma A549, melanoma B16, colorectal cancer HCT116, human hepatocellular carcinoma HepG2 cancer cell lines, as well as the non-cancerous LO2 cell line using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. While DPPA exhibited moderate anticancer activity toward A549, B16, HCT116 and HepG2 cells, complexes 2a, 2b, and 2c displayed remarkable efficacy against A549, B16, and HCT116 cells. The cell colonies and wound healing were investigated. Moreover, various aspects of the anticancer mechanisms were explored. The cell cycle analyses revealed that the complexes block cell proliferation of A549 cells during the S phase. Complex 2c induce an early apoptosis, while 2a and 2b cause a late apoptosis. The interaction of 2a, 2b and 2c with endoplasmic reticulum and mitochondria was identified, leading to elevated ROS and Ca2+ amounts. This resulted in a reduced mitochondrial membrane potential, mitochondrial permeability transition pore opening, and an increase of cytochrome c. Also, ferroptosis was investigated through measurements of intracellular glutathione (GSH), malondialdehyde (MDA), and recombinant glutathione peroxidase (GPX4) protein expression. The pyroptosis was explored via cell morphology, release of lactate dehydrogenase (LDH) and expression of pyroptosis-related proteins. RNA sequencing was applied to examine the signaling pathways. Western blot analyses illuminated that the complexes regulate the expression of Bcl-2 family proteins. Additionally, an in vivo antitumor study demonstrated that complex 2c exhibited a remarkable inhibitory rate of 58.58% in restraining tumor growth. In summary, the findings collectively suggest that the iridium(III) complexes induce cell death via ferroptosis, apoptosis by a ROS-mediated mitochondrial dysfunction pathway and GSDMD-mediated pyroptosis. Show less

A series of rhenium(I) complexes of the type fac-[Re(CO)₃(N^N)L]^0/+, Re1-Re9, was synthesized, where N^N = benzimidazole-derived bidentate ligand with an ester functionality and L = chloride or pyridine-type ligand. The new compounds demonstrated potent activity toward ovarian A2780 cancer cells. The most active complexes, Re7-Re9, incorporating 4-NMe₂py, exhibited remarkable activity in 3D HeLa spheroids. The emission in the red region of Re9, which contains an electron-deficient benzothiazole moiety, allowed its operability as a bioimaging tool for in vitro and in vivo visualization. Re9 effectivity was tested in two different C. elegans tumoral strains, JK1466 and MT2124, to broaden the oncogenic pathways studied. The results showed that Re9 was able to reduce the tumor growth in both strains by increasing the ROS production inside the cells. Moreover, the selectivity of the compound toward cancerous cells was remarkable as it did not affect neither the development nor the progeny of the nematodes. Show less

Screening new drug-target interactions (DTIs) by traditional experimental methods is costly and time-consuming. Recent advances in knowledge graphs, chemical linear notations, and genomic data enable researchers to develop computational-based-DTI models, which play a pivotal role in drug repurposing and discovery. However, there still needs to develop a multimodal fusion DTI model that integrates available heterogeneous data into a unified framework. Show less

Tumor onset and its progression are strictly linked to its metabolic rewiring on the basis of the Warburg effect. In this context, fumarate emerged as a putative oncometabolite mediating cancer progression. Fumarate accumulation is usually driven by fumarate hydratase (FH) loss of function, the enzyme responsible for the reversible conversion of fumarate into malate. Fumarate accumulation acts as a double edge sword: on one hand it takes part in the metabolic rewiring of cancer cells, while on the other it also plays a crucial role in chromatin architecture reorganization. The latter is achieved by competing with a-ketoglutarate-dependent enzymes, eventually altering the cellular methylome profile, which in turn leads to its transcriptome modeling. Furthermore, in recent years, it has emerged that FH has an ability to recruit DNA double strand breaks. The accumulation of fumarate into damaged sites might also determine the DNA repair pathway in charge for the seizure of the lesion, eventually affecting the mutational state of the cells. In this work, we aimed to review the current knowledge on the role of fumarate as an oncometabolite orchestrating the cellular epigenetic landscape and DNA repair machinery. Show less