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Abstract 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

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

Cancer remains a major global health burden, with rising incidence and mortality linked to aging populations and increased exposure to genotoxic agents. Oxidative stress plays a critical role in cancer development, progression, and resistance to therapy. The nuclear factor erythroid 2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1)-antioxidant response element (ARE) signaling pathway is central to maintaining redox balance by regulating the expression of antioxidant and detoxification genes. Under physiological conditions, this pathway protects cells from oxidative damage, however, sustained activation of NRF2 in cancer, often due to mutations in KEAP1, supports tumor cell survival, drug resistance, and metabolic reprogramming. Recent studies demonstrate that NRF2 enhances glutathione (GSH) synthesis, induces detoxifying enzymes, and upregulates drug efflux transporters, collectively contributing to resistance against chemotherapy and targeted therapies. The inhibition of NRF2 using small molecules or dietary phytochemicals has shown promise in restoring drug sensitivity in preclinical cancer models. This review highlights the dual role of NRF2 in redox regulation and cancer therapy, emphasizing its potential as a therapeutic target. While targeting NRF2 offers a novel approach to overcoming treatment resistance, further research is needed to enhance specificity and facilitate clinical translation. Show less

Mitochondria are associated with cellular energy metabolism, proliferation, and mode of death. Damage to mitochondrial DNA (mtDNA) greatly affects mitochondrial function by interfering with energy production and the signaling pathway. Monofunctional trinuclear platinum complex MTPC demonstrates different actions on the mtDNA of cancerous and normal cells. It severely impairs the integrity and function of mitochondria in the human lung cancer A549 cells, such as dissipating mitochondrial membrane potential, decreasing the copy number of mtDNA, interfering in nucleoid proteins and polymerase gamma gene, reducing adenosine triphosphate (ATP), and inducing mitophagy, whereas it barely affects the mtDNA of the human kidney 2 (HK-2) cells. Moreover, MTPC promotes the release of mtDNA into the cytosol and stimulates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, thus showing the potential to trigger antitumor immunity. MTPC displays significant cytotoxicity against A549 cells, while it exhibits weak toxicity toward HK-2 cells, therefore displaying great advantage to overcome the lingering nephrotoxicity of platinum anticancer drugs. Discrepant effects of a metal complex on mitochondria of different cells mean that targeting mitochondria has special significance in cancer therapy. Show less

Despite the widespread use of chemotherapeutic agents, their reliance on apoptosis often limits therapeutic efficacy and leads to drug resistance. To overcome these challenges, alternative cell death mechanisms such as cuproptosis have gained significant attention. While previous studies have primarily focused on incorporation of Cu into nanostructures, this work presents the first example of a molecular tripodal Cu(II) complex as a potent cuproptosis inducer. Herein, a series of tripodal Cu(II) complexes were chemically synthesized and biologically evaluated. The most promising compound demonstrated remarkable cytotoxicity in the low micromolar to nanomolar range. Mechanistic studies revealed that the compound catalytically produced hydroxyl radicals in the mitochondria of cancerous cells, causing protein oligomerization and the disruption of iron-sulfur cluster proteins, ultimately triggering cell death by cuproptosis. Contrary to traditional chemotherapeutic agents that cause reduction in tumor size, this compound induced the fragmentation of three-dimensional tumor spheroids. Show less

PT-112 is a novel small molecule exhibiting promising clinical activity in patients with solid tumors. PT-112 kills malignant cells by inhibiting ribosome biogenesis while promoting the emission of immunostimulatory signals. Accordingly, PT-112 is an authentic immunogenic cell death (ICD) inducer and synergizes with immune checkpoint inhibitors in preclinical models of mammary and colorectal carcinoma. Moreover, PT-112 monotherapy has led to durable clinical responses, some of which persisting after treatment discontinuation. Mitochondrial outer membrane permeabilization (MOMP) regulates the cytotoxicity and immunogenicity of various anticancer agents. Here, we harnessed mouse mammary carcinoma TS/A cells to test whether genetic alterations affecting MOMP influence PT-112 activity. As previously demonstrated, PT-112 elicited robust antiproliferative and cytotoxic effects against TS/A cells, which were preceded by the ICD-associated exposure of calreticulin (CALR) on the cell surface, and accompanied by the release of HMGB1 in the culture supernatant. TS/A cells responding to PT-112 also exhibited eIF2α phosphorylation and cytosolic mtDNA accumulation, secreted type I IFN, and exposed MHC Class I molecules as well as the co-inhibitory ligand PD-L1 on their surface. Acute cytotoxicity and HMGB1 release caused by PT-112 in TS/A cells were influenced by MOMP competence. Conversely, PT-112 retained antiproliferative effects and its capacity to drive type I IFN secretion as well as CALR, MHC Class I and PD-L1 exposure on the cell surface irrespective of MOMP defects. These data indicate a partial involvement of MOMP in the mechanisms of action of PT-112, suggesting that PT-112 is active across various tumor types, including malignancies with MOMP defects. Show less

Received: 25 June 2025 Revised: 8 August 2025 Accepted: 13 August 2025 Published: 14 August 2025 Citation: Jin, Z.; Zhang, Q.; Pan, Y.; Chen, H.; Zhou, K.; Cai, H.; Huang, P. Roles and Prospective Applications of Ferroptosis Suppressor Protein 1 (FSP1) in Malignant Tumor Treatment. Curr. Oncol. 2025, 32, 456. https:// doi.org/10.3390/curroncol32080456 Show less

Abstract Complex compounds [CuL(phen)(H2O)(NO3)]NO3 (1), [CuL(bipy)(NO3)2]·2EtOH (2), [CuL2(H2O)2 (NO3)2] (2a), [CuL(dmbipy)(NO3)2]·3EtOH (3), and [CuL2(NO3)2] (3a), where L is 3-(5-phenyl-2H-tetrazol-2-yl)pyridine, phen is 1,10-phenanthroline, bipy is 2,2′-bipyridine, and dmbipy is 4,4′-dimethyl-2,2′-bipyridine, are obtained and structurally characterized. It is shown that L behaves as the monodentate ligand being coordinated by the nitrogen atom of the pyridine ring. The coordination polyhedron made of copper atoms is a square pyramid in complexes 1 and 3, a distorted octahedron and a distorted square in complexes 2a and 3a respectively. Complex 1 is characterized by the elemental analysis, powder X-ray diffraction, and IR spectroscopy. Furthermore, its cytotoxic properties are studied on human larynx carcinoma (Hep2), breast adenocarcinoma (MCF7), and non-tumor human fibroblast (MRC5) cell lines. Complex 1 is shown to exhibit the pronounced cytotoxic action (LC50(Hep2) = 4.1±0.4 µM and LC50(MCF7) = 4.9±0.1 µM), however, does not exhibit selectivity against tumor cell lines (LC50(MRC5) = = 3.06 ±0.02 µM). 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

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

AbstractPhotoactivatable metal complexes offer the prospect of novel drugs with low side effects and new mechanisms of action to combat resistance to current therapy. We highlight recent progress in the design of platinum, ruthenium, iridium, gold and other transition metal complexes, especially for applications as anticancer and anti‐infective agents. In particular, understanding excited state chemistry related to identification of the bioactive species (excited state metallomics/pharmacophores) is important. Photoactivatable metallodrugs are classified here as photocatalysts, photorelease agents and ligand‐activated agents. Their activation wavelengths, cellular mechanisms of action, experimental and theoretical metallomics of excited states and photoproducts are discussed to explore new strategies for the design and investigation of photoactivatable metallodrugs. These photoactivatable metallodrugs have potential in clinical applications of Photodynamic Therapy (PDT), Photoactivated Chemotherapy (PACT) and Photothermal Therapy (PTT). Show less

A comprehensive review of metal-based inducers of immunogenic cell death (ICD), their design strategies, molecular mechanisms to trigger ICD, subsequent protective antitumor immune responses, as well as validation approaches. Show less

Photodynamic therapy (PDT) is a promising strategy for head and neck squamous cell carcinoma (HNSCC), but the immune consequences of tumor cell death remain incompletely understood. We compared two ruthenium(II) polypyridine photosensitizers (PSs) in HNSCC models and found that both were potently phototoxic (nanomolar IC₅₀s), triggered diverse cell death pathways (including autophagy and ferroptosis), and promoted hallmark danger signals of immunogenic cell death (ICD). Strikingly, only one PS induced apoptosis and strong endoplasmic reticulum (ER) stress, yet paradoxically led to immune tolerance in vivo. Conversely, the PS that did not induce apoptotic cell death with milder stress responses resulted in a better antitumor immunity in vivo. These unexpected findings challenge the prevailing view that PDT-triggered apoptosis and ER stress are essential for ICD. Our study underscores the complexity of PDT-induced cell death balance and immunogenic signals and highlights the need to redefine ICD-inducing criteria for the rational design of next-generation PSs. Show less

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

Photocatalytic cancer therapy (PCT) has emerged as a cutting-edge anticancer mechanism of action, harnessing light energy to mediate the catalytic oxidation of intracellular substrates. PCT is of significant current importance due to its potential to address the limitations of conventional chemotherapy, particularly drug resistance and side effects. This approach offers a noninvasive, targeted cancer treatment option by utilizing metal-based photocatalysts to induce redox and metabolic disorders within cancer cells. The photocatalysts disrupt the cancer cell metabolism by converting NADH/NAD(P)H to NAD⁺/NAD(P)⁺ via catalytic photoredox processes, altering intracellular NAD⁺/NADH or NAD(P)⁺/NAD(P)H ratios, which are crucial for cellular metabolism. Ir(III), Ru(II), Re(I), and Os(II) photocatalysts demonstrated promising PCT efficacy. Despite these developments, gaps remain in the literature for translating this new anticancer mechanism into clinical trials. This Perspective critically examines the developments in this research area and provides future directions for designing efficient photocatalysts for PCT. Show less

Oxaliplatin-based chemotherapy has proven to be one of the most effective treatments for advanced or metastatic colorectal cancer. However, increasing clinical resistance to oxaliplatin poses unprecedented challenges for both patients and clinicians. Despite extensive efforts to combat this issue, to date, no new molecules have been discovered that can successfully replace oxaliplatin. With the aim of developing a new generation of Pt(II)-based anticancer agents in response to the challenges of oxaliplatin-induced drug resistance, we performed a systematic screening of new Pt(II)-complexes with a quantitative structure-activity relationship (QSAR) study based on their antiresistance activity against oxaliplatin-resistant colon cancer cells. The results revealed that both the structure and chirality of the chelating ligand had a significant impact on the antiresistance properties of the Pt(II)-complexes. Our study culminated in the identification of chiral R-binaphthyldiamine-ligated Pt(II)-malonatoglycoconjugates that can completely counteract oxaliplatin resistance with excellent in vitro and in vivo potency. Show less

Pd–aryl complexes bearing a wide range of disphosphine, aryl and halide ligands were synthesized. Their remarkable in vitro and ex vivo anticancer activity seems to involve DNA as the main biotarget and an intrinsic apoptotic cell death mechanism. Show less

Iridium(III) complexes nowadays became rising stars in various health-related applications. Thus, there is a necessity to assess cytotoxicity of the synthesized molecules against cancer/normal cell lines. In this report, we present a dataset of 2694 experimental cytotoxicity values of 803 iridium complexes against 127 different cell lines. We specify the experimental conditions and provide representation of the complexes molecules in machine-readable format. The dataset provides a starting point for exploration of new iridium-based cellular probes and opens new possibilities for predictions of toxicities and data-driven generation of new organometallic anticancer agents. Show less

Over the past three decades, high-throughput phenotypic cancer cell line screens have revealed unanticipated small-molecule activities and illuminated connections between tumor genotypes and anticancer efficacy. Founded in 1984, the National Cancer Institute's "NCI60" screen laid the conceptual groundwork for the contemporary landscape of phenotypic drug discovery. NCI60 first operated as a primary bioactivity screen, but molecular characterization of the NCI60 cell line panel and development of a small-molecule sensitivity pattern recognition algorithm (called "COMPARE") have enabled subsequent studies into drug mechanisms of action and biomarker identification. In this issue of Cancer Research, Kunkel and colleagues report an updated version of the NCI60 screen, dubbed "HTS384" NCI60, that better aligns with current cell proliferation assay standards and has higher throughput. Changes include the use of a 384-well plate format, automated laboratory equipment, 3 days of compound exposure, and a CellTiter-Glo luminescent endpoint. To confirm that data from the HTS384 and classic NCI60 screen are comparable, the authors tested a library of 1,003 anticancer agents using both protocols and applied COMPARE to analyze patterns of cell line sensitivities. More than three dozen groups of targeted therapies showed high comparability between screens. Modernization of NCI60, and closer integration with other large-scale pharmacogenomic screens and molecular feature sets, will help this public screening service remain pertinent for cancer drug discovery efforts for years to come. See related article by Kunkel et al., p. 2403. Show less

Background

Immunogenic cell death (ICD) inducers are often identified in phenotypic screening campaigns by the release or surface exposure of various danger-associated molecular patterns (DAMPs) from malignant cells. This study aimed to streamline the identification of ICD inducers by leveraging cellular morphological correlates of ICD, specifically the condensation of nucleoli (CON).

Methods

We applied artificial intelligence (AI)-based imaging analyses to Cell Paint-stained cells exposed to drug libraries, identifying CON as a marker for ICD. CON was characterized using SYTO 14 fluorescent staining and holotomographic microscopy, and visualized by AI-deconvoluted transmitted light microscopy. A neural network-based quantitative structure-activity relationship (QSAR) model was trained to link molecular descriptors of compounds to the CON phenotype, and the classifier was validated using an independent dataset from the NCI-curated mechanistic collection of anticancer agents.

Results

CON strongly correlated with the inhibition of DNA-to-RNA transcription. Cytotoxic drugs that inhibit RNA synthesis without causing DNA damage were as effective as conventional cytotoxicants in inducing ICD, as demonstrated by DAMPs release/exposure and vaccination efficacy in mice. The QSAR classifier successfully predicted drugs with a high likelihood of inducing CON.

Conclusions

We developed AI-based algorithms for predicting CON-inducing drugs based on molecular descriptors and their validation using automated micrographs analysis, offering a new approach for screening ICD inducers with minimized adverse effects in cancer therapy. Show less

Copper is a necessary micronutrient for maintaining the well-being of the human body. The biological activity of organic ligands, especially their anticancer activity, is often enhanced when they coordinate with copper(I) and (II) ions. Copper and its compounds are capable of inducing tumor cell death through various mechanisms of action, including activation of apoptosis signaling pathways by reactive oxygen species (ROS), inhibition of angiogenesis, induction of cuproptosis, and paraptosis. Some of the copper complexes are currently being evaluated in clinical trials for their ability to map tumor hypoxia in various cancers, including locally advanced rectal cancer and bulky tumors. Several studies have shown that copper nanoparticles can be used as effective agents in chemodynamic therapy, phototherapy, hyperthermia, and immunotherapy. Despite the promising anticancer activity of copper-based compounds, their use in clinical trials is subject to certain limitations. Elevated copper concentrations may promote tumor growth, angiogenesis, and metastasis by affecting cellular processes. Show less

The stepwise, one-pot synthesis of heterobimetallic carbene gold(i) platinum(ii) complexes from readily available starting materials is presented. The protecting group free methodology is based on the graduated nucleophilicities of aliphatic and aromatic amines as linkers between both metal centers. This enables the selective, sequential installation of the metal fragments. In addition, the obtained complexes were tested as potential anticancer agents and directly compared to their gold(i) palladium(ii) counterparts. Show less

PT-112 is a novel immunogenic cell death (ICD)-inducing small molecule currently under Phase 2 clinical development, including in metastatic castration-resistant prostate cancer (mCRPC), an immunologically cold and heterogeneous disease state in need of novel therapeutic approaches. PT-112 has been shown to cause ribosome biogenesis inhibition and organelle stress followed by ICD in cancer cells, culminating in anticancer immunity. In addition, clinical evidence of PT-112-driven immune effects has been observed in patient immunoprofiling. Given the unmet need for immune-based therapies in prostate cancer, along with a Phase I study (NCT#02266745) showing PT-112 activity in mCRPC patients, we investigated PT-112 effects in a panel of human prostate cancer cell lines. PT-112 demonstrated cancer cell selectivity, inhibiting cell growth and leading to cell death in prostate cancer cells without affecting the non-tumorigenic epithelial prostate cell line RWPE-1 at the concentrations tested. PT-112 also caused caspase-3 activation, as well as stress features in mitochondria including ROS generation, compromised membrane integrity, altered respiration, and morphological changes. Moreover, PT-112 induced damage-associated molecular pattern (DAMP) release, the first demonstration of ICD in human cancer cell lines, in addition to autophagy initiation across the panel. Taken together, PT-112 caused selective stress, growth inhibition and death in human prostate cancer cell lines. Our data provide additional insight into mitochondrial stress and ICD in response to PT-112. PT-112 anticancer immunogenicity could have clinical applications and is currently under investigation in a Phase 2 mCRPC study. Show less