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Mitochondria are the energy production centers in cells and have unique genetic information. Due to the irreplaceable function of mitochondria, mitochondrial dysfunction often leads to pathological changes. Mitochondrial dysfunction induces an imbalance between oxidation and antioxidation, mitochondrial DNA (mtDNA) damage, mitochondrial dynamics dysregulation, and changes in mitophagy. It results in oxidative stress due to excessive reactive oxygen species (ROS) generation, which contributes to cell damage and death. Mitochondrial dysfunction can also trigger inflammation through the activation of damage-associated molecular patterns (DAMPs), inflammasomes and inflammatory cells. Besides, mitochondrial alterations in the functional regulation, energy metabolism and genetic stability accompany the aging process, and there has been a lot of evidence suggesting that oxidative stress and inflammation, both of which are associated with mitochondrial dysfunction, are predisposing factors of aging. Therefore, this review hypothesizes that mitochondria serve as central hubs regulating oxidative stress, inflammation, and aging, and their dysfunction contributes to various diseases, including cancers, cardiovascular diseases, neurodegenerative disorders, metabolic diseases, sepsis, ocular pathologies, liver diseases, and autoimmune conditions. Moreover, we outline therapies aimed at various mitochondrial dysfunctions, highlighting their performance in animal models and human trials. Additionally, we focus on the limitations of mitochondrial therapy in clinical applications, and discuss potential future research directions for mitochondrial therapy. Show less

Copper is a trace element which is essential for biological organisms, and its homeostatic balance is important for living organisms to maintain the normal function. When the copper homeostasis is disordered, the cellular function and structure will be disrupted. Excess copper cause oxidative stress and DNA damage in cells, thereby inducing regulated cell death such as apoptosis and necroptosis. Excess copper in mitochondria can bind to lipoylated proteins in the tricarboxylic acid (TCA) cycle and cause them to aggregate, resulting in proteotoxic stress and eliciting a novel cell death modality: cuproptosis. Cancer cells have a greater demand for copper compared to normal tissue, and high levels of copper ions are closely associated with tumour proliferation and metastasis. The anti-tumor mechanisms of copper include the production of oxidative stress, inhibition of the ubiquitin–proteasome system, suppression of angiogenesis, and induction of copper-dependent cell death. Targeting copper is one of the current directions in oncology research, including the use of copper ion carriers to increase intracellular copper levels to induce oxidative stress and cuproptosis, as well as the use of copper ion chelators to reduce copper bioavailability. However, copper complexes have certain toxicity, so their biosafety needs to be improved. Emerging nanotechnology is expected to solve this problem by utilizing copper-based nanomaterials (Cu-based NMs) to deliver copper ions and a variety of drugs with different functions, thereby improving the anti-tumor efficacy and reducing the side effects. Therefore, a thorough understanding of copper metabolic processes and the mechanism of cuproptosis will greatly benefit anti-tumor therapy. This review summarizes the processes of copper metabolism and the mechanism of cuproptosis. In addition, we discuss the current anti-tumor paradigms related to copper, we also discuss current nanotherapeutic approaches to copper mortality and provide prospective insights into the future copper-mediated cancer therapy. 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

Tumour cells undergo profound changes in their metabolism, but targeting these metabolic pathways requires understanding of the impact on immune cells as well as cancer cells. This Review discusses how metabolic pathways in cancer and immune cells shape the tumour microenvironment and describes metabolic modulators and dietary nutrients developed to improve the anticancer immune response. Show less

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

Abstract The negatively charged aminophospholipid, phosphatidylserine (PS), is typically restricted to the inner leaflet of the plasma membrane under normal, healthy physiological conditions. PS is irreversibly externalized during apoptosis, where it serves as a signal for elimination by efferocytosis. PS is also reversibly and transiently externalized during cell activation such as platelet and immune cell activation. These events associated with physiological PS externalization are tightly controlled by the regulated activation of flippases and scramblases. Indeed, improper regulation of PS externalization results in thrombotic diseases such as Scott Syndrome, a defect in coagulation and thrombin production, and in the case of efferocytosis, can result in autoimmunity such as systemic lupus erythematosus (SLE) when PS-mediated apoptosis and efferocytosis fails. The physiological regulation of PS is also perturbed in cancer and during viral infection, whereby PS becomes persistently exposed on the surface of such stressed and diseased cells, which can lead to chronic thrombosis and chronic immune evasion. In this review, we summarize evidence for the dysregulation of PS with a main focus on cancer biology and the pathogenic mechanisms for immune evasion and signaling by PS, as well as the discussion of new therapeutic strategies aimed to target externalized PS. We posit that chronic PS externalization is a universal and agnostic marker for diseased tissues, and in cancer, likely reflects a cell intrinsic form of immune escape. The continued development of new therapeutic strategies for targeting PS also provides rationale for their co-utility as adjuvants and with immune checkpoint therapeutics. Show less

The convergence of artificial intelligence (AI) and genomics is redefining cancer drug discovery by facilitating the development of personalized and effective therapies. This review examines the transformative role of AI technologies, including deep learning and advanced data analytics, in accelerating key stages of the drug discovery process: target identification, drug design, clinical trial optimization, and drug response prediction. Cutting-edge tools such as DrugnomeAI and PandaOmics have made substantial contributions to therapeutic target identification, while AI's predictive capabilities are driving personalized treatment strategies. Additionally, advancements like AlphaFold highlight AI's capacity to address intricate challenges in drug development. However, the field faces significant challenges, including the management of large-scale genomic datasets and ethical concerns surrounding AI deployment in healthcare. This review underscores the promise of data-centric AI approaches and emphasizes the necessity of continued innovation and interdisciplinary collaboration. Together, AI and genomics are charting a path toward more precise, efficient, and transformative cancer therapeutics. Show less

Hypoxia is a common feature of solid tumors and is associated with a poor response to anticancer therapies. Hypoxia also induces metabolic changes, such as a switch to glycolysis. This glycolytic switch causes acidification of the tumor microenvironment (TME), thereby attenuating the anticancer immune response. A promising therapeutic strategy to reduce hypoxia and thereby sensitize tumors to irradiation and/or antitumor immune responses is pharmacological inhibition of oxidative phosphorylation (OXPHOS). Several OXPHOS inhibitors (OXPHOSi) have been tested in clinical trials. However, moderate responses and/or substantial toxicity have hampered clinical implementation. OXPHOSi tested in clinical trials inhibit the oxidative metabolism in tumor cells as well as healthy cells. Therefore, new strategies are needed to improve the efficacy of OXPHOSi while minimizing side effects. To enhance the therapeutic window, available OXPHOSi have, for instance, been conjugated to triphenylphosphonium to preferentially target the mitochondria of cancer cells, resulting in increased tumor uptake compared with healthy cells, as cancer cells have a higher mitochondrial membrane potential. However, OXPHOS inhibition also induces reactive oxygen species and subsequent antioxidant responses, which may influence the efficacy of therapies, such as platinum-based chemotherapy and radiotherapy. Here, we review the limitations of the clinically tested OXPHOSi metformin, atovaquone, tamoxifen, BAY 87-2243, and IACS-010759 and the potential of mitochondria-targeted OXPHOSi and their influence on reactive oxygen species production. Furthermore, the effect of the mitochondria-targeting moiety triphenylphosphonium on mitochondria is discussed as it affects mitochondrial bioenergetics. Show less

The classical view of protein function based on rigid, well-defined structures is being redefined by the emerging concept of intrinsic disorder. Conditionally disordered proteins (CDPs) represent a subset of cellular intrinsically disordered proteins (IDPs) that transition between ordered and disordered states in response to specific stimuli, such as redox changes, post-translational modifications, ligand binding, interaction with partners, or environmental stress. This review explores the diverse landscape of conditional disorder and encompasses cryptic or dormant disordered regions, redox-sensitive motifs, metamorphic proteins, and proteins exhibiting order–disorder–new order transitions. These dynamic transitions allow CDPs to perform specialized regulatory, signalling, and stress-responsive roles, which often act as interaction hubs in complex cellular networks. Importantly, conditional disorder is not an anomaly but a conserved and functionally relevant feature across many proteomes. We highlight mechanistic insights into disorder-to-order transitions and their implications for cellular plasticity, adaptability, and disease. We also discuss how the conformational heterogeneity of CDPs complicates structure-based drug design, while offering unique therapeutic opportunities. Future directions include the integration of advanced biophysical techniques, computational modelling, and profiling to map, characterize, and target CDPs with greater precision. Overall, understanding the molecular logics of the conditional disorder will open new frontiers in structural biology and offer a deeper appreciation of protein versatility beyond static structural paradigms. Show less

Regulatory T (Treg) cells play critical roles in maintaining immune tolerance and tissue homeostasis, but impede anti-tumor immunity. Recent work has established how Treg cells metabolically adapt within the tumor microenvironment (TME), and these adaptations frequently provide a functional advantage over effector T cells. Further, enhanced Treg cell function in the TME may contribute to the limited efficacy of current immunotherapies, especially immune checkpoint blockade (ICB). Here, we review recent progress in understanding mechanisms of Treg cell heterogeneity and function in tumors, with a particular focus on cellular metabolism as an underlying factor by which Treg cells are uniquely poised to thrive in the TME and contribute to tumorigenesis. We describe how cellular metabolism and nutrient or metabolic communication shape Treg cell lineage identity and function in the TME. We also discuss the interplay between ICB and Treg cell metabolism and function, and highlight current strategies targeting Treg cell metabolism specifically in the TME. Understanding metabolic control of intratumoral Treg cells provides excellent opportunities to uncover new or combination therapies for cancer. 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

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

Differential and even opposing functions of two major antioxidant transcription factors Nrf1 and Nrf2 (encoded by Nfe2l1 and Nfe2l2, respectively) are determined by distinctions in their tempospatial positioning, topological repartitioning, proteolytic processing, and biochemical modification, as well as in their shared evolutionary origin. As a matter of fact, the allelopathic potentials of Nrf1 and Nrf2 (both resembling two entangled 'Yin-Yang' quanta that comply with a dialectic law of the unity of opposites) are fulfilled to coordinately control redox physiological homeostasis so as to be maintained within the presetting thresholds. By putative exponential curves of redox stress and intrinsic anti-redox capability, there is inferable to exist a set point at approaching zero with the 'Golden Mean' for the healthy survival (i.e., dubbed the 'zero theory'). A bulk of the hitherto accumulating evidence demonstrates that the set point of redox homeostasis is dictated selectively by multi-hierarchical threshold settings, in which the living fossil-like Nrf1 acts as a robust indispensable determinon, whereas Nrf2 serves as a versatile chameleon-like master regulon, in governing the redox homeodynamic ranges. This is attributable to the facts that Nrf2 has exerted certain 'double-edged sword' effects on life process, whereas Nrf1 executes its essential physiobiological functions, along with unique pathophysiological phenotypes, by integrating its 'three-in-one' roles elicited as a specific triplet of direct sensor, transducer and effector within multi-hierarchical stress responsive signaling to redox metabolism and target gene reprogramming. Here, we also critically reviewed redox regulation of physio-pathological functions from the eco-evo-devo perspectives, through those coding rules (redox code, stress-coping code, and topogenetic code). The evolving concepts on stress and redox stress were also further revisited by scientific principles of physics and chemistry. Besides, several novel concepts such as oncoprotists, Reverse Central Dogma, and Grand Redox-Unifying Theory' (GRUT) of life, together with diffusive reactive species (DRS)-based murburn concept integrating all stochastic electron-, proton- and/or moiety-transfer reactive and interactive processes (e.g., PCHEMS), are introduced in this interdisciplinary and synthetic review. Show less

Oxidative stress appears to act globally and span body systems (e.g., nervous, immune, and endocrine). Currently, there is no single, generally-accepted measurement of oxidative stress. Many possible measurement approaches focus on the bottom-up analysis of individual molecules (e.g., reactive species, antioxidants, hormones or signaling molecules) or combinations of molecules (e.g., proteomics or metabolomics). Efforts to develop a global measurement of oxidative stress often detect a sample's ability to reduce a metal-ion (e.g., iron or copper) or quench a free radical. Here, we review results from a recently-developed iridium-reducing capacity assay (Ir-RCA) and suggest that this method offers several key benefits as a potential measurement of oxidative stress. First, the Ir-RCA employs simple optical and/or electrochemical measurements that can be extended to high throughput formats. Second, the Ir-RCA appears to be more sensitive than alternative global antioxidant assays. Third, the Ir-RCA measures stable molecular features of a sample. Fourth, the Ir-RCA has been "validated" by showing statistically significant differences in persons diagnosed with schizophrenia (N = 73) versus healthy controls (N = 45). Fifth, the Ir-RCA measurement of oxidative stress is "movable": psychosocial stressors can increase this measure of oxidative stress, while beneficial dietary interventions can decrease this measure of oxidative stress. Limitations and future directions for the Ir-RCA are discussed. Show less

Claudin (CLDN) proteins are extensively studied due to their critical role in maintaining tissue barriers and cell polarity. However, significant gaps remain in understanding the functional mechanisms of their sequence motifs and the molecular mechanisms of their interactions with other tight junction proteins. This review systematically examines the multifunctional properties of the CLDN protein family from the perspectives of sequence and structure. During evolution, CLDN family members have developed highly conserved structural features, particularly key conserved sites within the first extracellular loop (ECL1) and the C-terminal PDZ-binding domain, which play a central role in regulating the barrier function of tight junctions, ion selectivity, and protein-protein interactions. Furthermore, the distribution pattern of acidic and basic amino acids in ECL1 has been shown to directly determine ion selectivity and paracellular permeability. Meanwhile, the assembly and functional stability of tight junctions are precisely regulated by the C-terminal PDZ-binding domain through its interactions with the ZO protein family. Additionally, the study further elucidates how CLDN proteins modulate critical signaling pathways governing cellular proliferation, survival, and permeability, thereby participating in diverse physiological and pathological processes. These insights have deepened the understanding of the functional diversity of CLDN proteins and provided a new theoretical basis for developing disease diagnostic markers and designing targeted treatment strategies based on CLDN proteins. Show less

BACKGROUND: Globally, the onset and progression of multiple human diseases are associated with mitochondrial dysfunction and dysregulation of Ca2+ uptake dynamics mediated by the mitochondrial calcium uniporter (MCU) complex, which plays a key role in mitochondrial dysfunction. Despite relevant studies, the underlying pathophysiological mechanisms have not yet been fully elucidated. AIM OF REVIEW: This article provides an in-depth analysis of the current research status of the MCU complex, focusing on its molecular composition, regulatory mechanisms, and association with diseases. In addition, we conducted an in-depth analysis of the regulatory effects of agonists, inhibitors, and traditional Chinese medicine (TCM) monomers on the MCU complex and their application prospects in disease treatment. From the perspective of medicinal chemistry, we conducted an in-depth analysis of the structure-activity relationship between these small molecules and MCU and deduced potential pharmacophores and binding pockets. Simultaneously, key structural domains of the MCU complex in Homo sapiens were identified. We also studied the functional expression of the MCU complex in Drosophila, Zebrafish, and Caenorhabditis elegans. These analyses provide a basis for exploring potential treatment strategies targeting the MCU complex and provide strong support for the development of future precision medicine and treatments. KEY SCIENTIFIC CONCEPTS OF REVIEW: The MCU complex exhibits varying behavior across different tissues and plays various roles in metabolic functions. It consists of six MCU subunits, an essential MCU regulator (EMRE), and solute carrier 25A23 (SLC25A23). They regulate processes, such as mitochondrial Ca2+ (mCa2+) uptake, mitochondrial adenosine triphosphate (ATP) production, calcium dynamics, oxidative stress (OS), and cell death. Regulation makes it a potential target for treating diseases, especially cardiovascular diseases, neurodegenerative diseases, inflammatory diseases, metabolic diseases, and tumors. Show less

Mitochondrial outer membrane permeabilization (MOMP) refers to the increase in permeability of the mitochondrial outer membrane, allowing proteins, DNA, and other molecules to pass through the intermembrane space into the cytosol. As a crucial event in the induction of apoptosis, MOMP plays a significant role in regulating various forms of cell death, including apoptosis, ferroptosis, and pyroptosis. Importantly, MOMP is not a binary process of "all-or-nothing." Under sub-lethal stress stimuli, cells may experience a phenomenon referred to as minority MOMP (miMOMP), where only a subset of mitochondria undergo functional impairment, thereby disrupting the normal life cycle of the cell. This can lead to pathological and physiological changes such as tumor formation, cellular senescence, innate immune dysfunction, and chronic inflammation. This review focuses on the diversity of MOMP events to elucidate how varying degrees of MOMP under different stress conditions influence cell fate. Additionally, it summarizes the current research progress on novel antitumor therapeutic strategies targeting MOMP in clinical contexts. Show less

This Perspective discusses how elevated-temperature crystallography uncovers hidden dynamic states of protein, ligand and water molecules, expanding insights into the protein conformational landscape for drug discovery and design. Show less

Despite advances in understanding genetic susceptibility to cancer, much of cancer heritability remains unidentified. At the same time, the makeup of industrial chemicals in our environment only grows more complex. This gap in knowledge on cancer risk has prompted calls to expand cancer research to the comprehensive, discovery-based study of nongenetic environmental influences, conceptualized as the "exposome." 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

Tumor microenvironment (TME) denotes the non-cancerous cells and components presented in the tumor, including molecules produced and released by them. Interactions between cancer cells, immune cells, stromal cells, and the extracellular matrix within the TME create a dynamic ecosystem that can either promote or hinder tumor growth and spread. The TME plays a pivotal role in either promoting or inhibiting tumor growth and dissemination, making it a critical factor to consider in the development of effective cancer therapies. Understanding the intricate interplay within the TME is crucial for devising effective cancer therapies. Combination therapies involving inhibitors of immune checkpoint blockade (ICB), and/or chemotherapy now offer new approaches for cancer therapy. However, it remains uncertain how to best utilize these strategies in the context of the complex tumor microenvironment. Oncogene-driven changes in tumor cell metabolism can impact the TME to limit immune responses and present barriers to cancer therapy. Cellular and acellular components in tumor microenvironment can reprogram tumor initiation, growth, invasion, metastasis, and response to therapies. Components in the TME can reprogram tumor behavior and influence responses to treatments, facilitating immune evasion, nutrient deprivation, and therapeutic resistance. Moreover, the TME can influence angiogenesis, promoting the formation of blood vessels that sustain tumor growth. Notably, the TME facilitates immune evasion, establishes a nutrient-deprived milieu, and induces therapeutic resistance, hindering treatment efficacy. A paradigm shift from a cancer-centric model to a TME-centric one has revolutionized cancer research and treatment. However, effectively targeting specific cells or pathways within the TME remains a challenge, as the complexity of the TME poses hurdles in designing precise and effective therapies. This review highlights challenges in targeting the tumor microenvironment to achieve therapeutic efficacy; explore new approaches and technologies to better decipher the tumor microenvironment; and discuss strategies to intervene in the tumor microenvironment and maximize therapeutic benefits. Graphical Abstract 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

Since its discovery 30 years ago, NRF2 has emerged as a master regulator of cellular homeostasis and has been implicated in a broad range of pathologies. This Review analyses NRF2 regulation, signalling and cross-talk, and assesses the role of this transcription factor in health and disease. The development of therapeutic NRF2 modulators and the associated challenges are also discussed. 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

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

NRF2 is a redox-sensitive transcription factor that activates the expression of phase II detoxifying and antioxidant enzymes. In addition to maintaining redox homeostasis, NRF2 regulates various other processes, including metabolism, stem cell renewal, mitochondrial function, and proteostasis. NRF2 is considered a tumor suppressor because its activation by chemopreventive phytochemicals contributes to the detoxification of oxidants and electrophiles in normal cells. However, aberrant NRF2 activation occurs in cancer due to mutations in the KEAP1/NRF2 pathway, and it contributes to the generation of a tumor microenvironment that favors the proliferation, survival, and chemoresistance of cancer cells. In this review, we present the regulatory mechanisms of NRF2 and discuss how NRF2 activation contributes to chemoresistance. We also explain therapeutic strategies that exploit the vulnerabilities of NRF2-addicted cancer cells, providing NRF2 small-molecule inhibitors along with their mechanisms of action. Show less

Significant progress has been made in understanding the mechanism of transcription-coupled nucleotide excision repair (TC-NER); however, numerous aspects remain elusive, including TC-NER regulation, lesion-specific and cell type-specific complex composition, structural insights, and lesion removal dynamics in living cells. This review summarizes and discusses recent advancements in TC-NER, focusing on newly identified interactors, mechanistic insights from cryo-electron microscopy (Cryo-EM) studies and live cell imaging, and the contribution of post-translational modifications (PTMs), such as ubiquitin, in regulating TC-NER. Furthermore, we elaborate on the consequences of TC-NER deficiencies and address the role of accumulated damage and persistent lesion-stalled RNA polymerase II (Pol II) as major drivers of the disease phenotype of Cockayne syndrome (CS) and its related disorders. In this context, we also discuss the severe effects of transcription-blocking lesions (TBLs) on neurons, highlighting their susceptibility to damage. Lastly, we explore the potential of investigating three-dimensional (3D) chromatin structure and phase separation to uncover further insights into this essential DNA repair pathway. 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