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Polyamines, namely putrescine, spermidine and spermine, are involved in multiple molecular pathways through their ability to bind nucleic acids and modulate protein stability. Their intracellular level is regulated through biosynthesis, catabolism and uptake from the extracellular milieu and the disruption of their homeostasis contributes to a variety of human disorders including cancer, as mainly described in solid tumors. Recently, there is an increasing interest in understanding polyamine functions in acute leukemias, due to the linkage between leukemic gene drivers, polyamine metabolism alterations and epigenetic defects. In particular, polyamine involvement in the regulation of acetylation and methylation is clinically relevant since epigenetic drugs are currently the backbone of novel therapeutic combinations, especially in acute myeloid leukemia (AML). With the exception of methylthioadenosine phosphorylase (MTAP), the enzyme leading to methionine regeneration that is frequently deleted in acute lymphoblastic leukemia (ALL), genes involved in polyamine metabolism and the interconnected methionine and arginine pathways are rarely targets of genetic lesions in acute leukemias. Conversely, functional alterations, including elevated polyamine levels and deregulated activity of enzymes involved in their metabolism, have been recently reported in leukemic cells. Notably, the polyamine catabolic enzyme spermidine/spermine N1 acetyltransferase (SAT1) that is overexpressed in AML and associated with a myeloproliferative phenotype, is a tumor suppressor gene in ALL, suggesting diverse mechanisms of action across hematological malignancies according to the lineage commitment and the differentiation stage. In light of the promising results achieved in AML and ALL by selective targeting of protein arginine methyltransferase 5 (PRMT5) and methionine adenosyltransferase 2A (MAT2A), two enzymes at the crossroad between polyamine metabolism and protein methylation, in this review we examine and discuss the role of polyamines in epigenetic regulation and other biological processes supporting leukemic cell survival, proliferation and differentiation, which provides the opportunity to discover additional polyamine-related targets and design novel therapeutic combinations. Show less

Nucleotide excision repair (NER) is a universal cut-and-paste DNA repair mechanism that corrects bulky DNA lesions such as those caused by UV radiation, environmental mutagens, and some chemotherapy drugs. In this review, we focus on the human transcription/DNA repair factor TFIIH, a key player of the NER pathway in eukaryotes. This 10-subunit multiprotein complex notably verifies the presence of a lesion and opens the DNA around the damage via its XPB and XPD subunits, two proteins identified in patients suffering from Xeroderma Pigmentosum syndrome. Isolated as a class II gene transcription factor in the late 1980s, TFIIH is a prototypic molecular machine that plays an essential role in both DNA repair and transcription initiation and harbors a DNA helicase, a DNA translocase, and kinase activity. More recently, TFIIH subunits have been identified as participating in other cellular processes, including chromosome segregation during mitosis, maintenance of mitochondrial DNA integrity, and telomere replication. 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

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

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

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

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

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

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

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

Necroptosis, a non-apoptotic mode of programmed cell death, is characterized by the disintegration of the plasma membrane, ultimately leading to cell perforation and rupture. Recent studies have disclosed the mechanism of necroptosis and its intimate link with nanomaterials. Nanomedicine represents a novel approach in the development of therapeutic agents utilizing nanomaterials to treat a range of cancers with high efficacy. This article provides an overview of the primary mechanism behind necroptosis, the current research progress in nanomaterials, their potential use in various diseases—notably cancer, safety precautions, and prospects. The goal is to aid in the development of nanomaterials for cancer treatment. 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

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

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

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

Abstract In October 2024 we celebrated the 15th anniversary of the first launch of ChEMBL, Europe’s most impactful, open-access drug discovery database, hosted by EMBL’s European Bioinformatics Institute (EMBL-EBI). This is a good moment to reflect on ChEMBL’s history, the role that ChEMBL plays in Cheminformatics and Drug Discovery as well as innovations accelerated using data extracted from it. The review closes by discussing current challenges and possible directions that need to be taken to guarantee that ChEMBL continues to be the pioneering resource for highly curated, open bioactivity data on the European continent and beyond. Show less

Mitochondria are dynamic organelles that are essential for cellular energy generation, metabolic regulation, and signal transduction. Their structural complexity enables adaptive responses to diverse physiological demands. In cancer, mitochondria orchestrate multiple cellular processes critical to tumor development. Metabolic reprogramming enables cancer cells to exploit aerobic glycolysis, glutamine metabolism, and lipid alterations, supporting uncontrolled growth, survival, and treatment resistance. Genetic and epigenetic alterations in mitochondrial and nuclear DNA disrupt oxidative phosphorylation, tricarboxylic acid cycle dynamics, and redox homeostasis, driving oncogenic progression. Mitochondrial dysfunction in tumors is highly heterogeneous, influencing disease phenotypes and treatment responses across cancer types. Within the tumor microenvironment, mitochondria profoundly impact immune responses by modulating T-cell survival and function, macrophage polarization, NK cell cytotoxicity, and neutrophil activation. They also mediate stromal cell functions, particularly in cancer-associated fibroblasts and tumor endothelial cells. Although targeting mitochondrial function represents a promising therapeutic strategy, mitochondrial heterogeneity and adaptive resistance mechanisms complicate interventional approaches. Advances in mitochondrial genome editing, proteomics, and circulating mitochondrial DNA analysis have enhanced tumor diagnostic precision. This review synthesizes the developmental landscape of mitochondrial research in cancer, comprehensively summarizing mitochondrial structural dynamics, metabolic plasticity, signaling networks, and interactions with the tumor microenvironment. Finally, we discuss the translational challenges in developing effective mitochondria-based cancer interventions. 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

[Ru(bpy)₃]²⁺, tris(bipyridine)ruthenium(II), is a popular transition metal complex whose favorable photophysical properties have afforded it a central place in inorganic photochemistry and various related fields. In this perspective, in contrast to the large number of extant technical reviews, we instead note critical developments from a historical context. Of particular note are relatively lesser-known investigations in the field of analytical chemistry that predate the complex's rise to prominence as a photosensitizer. Recent studies that revisit the complex's own fundamental photophysics are also highlighted. Thus, in addition to serving as a proverbial almanac for the complex's rich history, this condensed perspective portends yet more fruitful lives for research into [Ru(bpy)₃]²⁺, despite the many already lived. Show less

This Review explores the state-of-the-art applications of artificial intelligence in small-molecule drug development, from target identification and drug synthesis up to clinical trial design and conduct. Show less

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

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

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

Lipid peroxidation stands as a prominent hallmark and a prerequisite for the onset of ferroptosis. Lipid metabolism holds a pivotal role in regulating this process, forming the metabolic foundation for cellular sensitivity to ferroptosis. Studies in lipid metabolomics reveal that the activation of Polyunsaturated fatty acids (PUFA), specifically arachidonic acid and adrenoic acid (AdA), mediated by acyl-CoA synthetase long-chain family member 4 (ACSL4), represents a critical step in generating lipid peroxidation substrates. The expression level or enzymatic activity of ACSL4 emerges as a potential indicator of cellular susceptibility to ferroptosis. Additionally, other members of the ACSL family can indirectly influence the occurrence of ferroptosis by modifying the fatty acid composition of the cell membrane. Given the high expression of ACSL4 in various human tumors, targeting lipid peroxidation with ACSL4 as the focal point may pave a new path in tumor therapy. This article provides a brief overview of the primary structure and function of ACSL4, its role in lipid peroxidation, and summarizes the current advancements in drug development targeting ACSL4 and lipid peroxidation. Show less

Lung cancer remains the leading cause of cancer-related mortality globally, necessitating the continual exploration of novel therapeutic targets. The phosphoinositide 3-kinase (PI3K) signaling pathway plays a pivotal role in oncogenic processes, including cell growth, survival, metabolism and immune modulation. This comprehensive review delineates the distinct roles of PI3K subtypes—PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ—in lung cancer pathogenesis and progression. We evaluate the current landscape of PI3K inhibitors, transitioning from non-selective early-generation compounds to isoform-specific agents, highlighting their clinical efficacy, resistance mechanisms and potential combination strategies. Furthermore, the intricate interplay between PI3K signaling and the tumor immune microenvironment is explored, elucidating how PI3K modulation can enhance immunotherapeutic responses. Metabolic reprogramming driven by PI3K signaling is also dissected, revealing vulnerabilities that can be therapeutically exploited. Despite promising advancements, challenges such as therapeutic resistance and adverse effects underscore the need for personalized medicine approaches and the development of next-generation inhibitors. This review underscores the multifaceted role of PI3K in lung cancer and advocates for integrated strategies to harness its full therapeutic potential, paving the way for improved patient outcomes. 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

Structure-based drug design is rapidly evolving, driven by advances in both physics-based and knowledge-based methods. These computational approaches are increasingly integrated across all stages of drug discovery. Despite remarkable progress, challenges remain in achieving accuracy, generalizability, computational efficiency, and chemical synthesizability. In this review, we provide a critical overview of advances, strengths, and limitations of recent methods. We also discuss synergies between the two concepts that hold promises for future advancements towards their practical applicability. 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

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