Search Results (869)

p53 tumor suppressor evolved as a critical player in navigating the response to environmental stresses such as DNA or oxidative damage and drives cell fate by governing life and death decisions. The p53 protein is encoded by the most commonly mutated gene in human cancers. TP53 gene mutations are associated with worse prognosis and refractory and relapsed disease. The most prevalent mutations are of the missense type and often result in disruption of the DNA-binding capacity and transcription activity. In healthy cells, p53 protein is tightly regulated by its E3 ubiquitin ligase, MDM2 (HDM2), its own transcription target. Mutant p53, therefore, escapes the regulation by the negative feedback loop and is often found upregulated in cancer cells. The efforts to exploit wild-type and mutant p53 for precision oncology have been ongoing in the last two decades yet have not been successful. A recently reported strategy to target TP53-mutant cancers leverages induced proximity, utilizing the high cellular abundance of mutant p53 as a scaffold to concentrate a small-molecule inhibitor against an essential survival protein. This strategy relies on the Regulated Induced Proximity TArgeting Chimera (RIPTAC). Given the recent FDA approval of the first chimeric drug, vepdegestrant, killing by proximity might turn out to be a promising medical advancement for precision oncology. Full article

Myeloid-derived suppressor cells (MDSCs) are a class of immature, heterogenous, and functionally immunosuppressive myeloid progenitors that are expanded in malignant disease including glioblastoma (GBM). Extensive preclinical evaluation of GBM has revealed that MDSCs express multiple different chemokine and cytokine receptors that facilitate their entry, infiltration, expansion and immunosuppression of antitumor immunity in the tumor microenvironment. Additionally, translational investigation of approaches that target MDSCs directly or indirectly through immune remodeling has yielded promising effects that are under clinical trial investigation. Given the immunosuppressive phenotype of high-grade gliomas like GBM, the removal of MDSCs represents a clinically relevant strategy to enhance immune responses against neoplastic cells. In this review, we provide a comprehensive summary of MDSCs in GBM, emphasizing clinical observations and large-scale multi-omics studies that position MDSCs at the nexus of GBM immunosuppression. Next, we provide detailed coverage of multiple chemokines, cytokines, and growth factors that are relevant to MDSC migration, survival and expansion in GBM along with commentary on the associated receptors. Lastly, we discuss therapeutic approaches that directly target MDSCs as a strategy to improve immune responses against malignant brains and observations on the changes to MDSCs in the tumor microenvironment after immunotherapy. Our review serves as a valuable resource for the neuro-oncology research space, updating scientists and clinicians on a cell central to the biology and therapeutic targeting of GBM. Full article

Human papillomavirus (HPV) has become a leading cause of oropharyngeal cancers, alongside well-known risk factors such as tobacco and alcohol use. Currently, HPV-positive oropharyngeal squamous cell carcinoma (HPV+ OPSCC) has increased significantly in developed countries, with HPV-16 being the most common high-risk subtype. Clinically, HPV+ OPSCC shows clear differences in prognosis compared to HPV-negative tumors, particularly regarding survival rates and treatment responses. Patients with HPV+ OPSCC tend to have notably better survival outcomes and a more favorable outlook. Strong evidence indicates that HPV-related oropharyngeal cancers represent a distinct epidemiological, clinical, and molecular group, setting them apart from non-HPV-related cancers. As a result, treatment strategies for these subtypes should follow specific clinical protocols to optimize outcomes. Additionally, the viral oncoproteins E6 and E7, which systematically disrupt host tumor-suppressor networks, provide strong reasons for targeted phytotherapeutic interventions. Therefore, there is increasing interest in exploring plant bioactive compounds with promising anti-HPV and anticancer effects that target key oncogenic pathways. This review aims to compile the latest data on bioactive phytochemicals with mechanistic evidence in HPV+ OPSCC, highlight their molecular interactions across oncogenic signaling pathways, and discuss evidence-based findings focusing on research published from 2000 to 2025. Full article

Osteosarcoma (OS) is the most common primary bone cancer in adolescents and young adults. Despite tremendous preclinical and clinical efforts to advance therapy for OS, the standard of care, consisting of surgical resection and pre- and postoperative chemotherapy, has remained unchanged for over 40 years. Growing molecular understanding of OS highlights tumor heterogeneity as a major obstacle to therapeutic advances. In this narrative review, we comprehensively discuss current evidence of OS heterogeneity and strategies to overcome the barrier. Evidence shows that OS heterogeneity is multifactorial: it retains complex and dynamic somatic genomics, including genomic instability, alterations in tumor suppressors, and amplification/overexpression of oncogenes such as MYC. The tumor is associated with various germline vulnerabilities. OS’s tumor microenvironment has intense cellular and spatial diversity, which significantly shapes its heterogeneity. The effects of lineage plasticity, as well as epigenetic and metabolomic mechanisms, on OS heterogeneity are under study. To overcome this extreme heterogeneity, the therapeutic strategies for OS must be comprehensive and diversified. While surgical resection remains a mainstay of treatment, efforts to identify actionable biomarkers that guide risk stratification and therapy are ongoing. Diverse preclinical models offer insights into OS biology and novel therapeutics. To enhance combinational therapy for OS, various agents, including multi-targeted receptor tyrosine kinase inhibitors, immunotherapies, and epigenetic and metabolic modifiers, are being investigated. Distinctive efforts are continuing to establish maintenance therapy for OS. In summary, elucidating the complex drivers of OS heterogeneity, together with the development of multifaceted strategies to address them, is critical to accelerating therapeutic progress in OS. Full article

Immune checkpoint inhibitors targeting the PD-1 (Programmed Cell Death Protein 1)/PD-L1 (Programmed Death-Ligand 1) axis have transformed cancer therapeutics, yet their efficacy in gynecologic malignancies particularly high-grade serous ovarian carcinoma remains disappointingly limited. This therapeutic resistance stems from a highly orchestrated, multidimensional immunosuppressive tumor microenvironment (TME) characterized by the convergent actions of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and an inhibitory cytokine network (IL-10, TGF-β, VEGF). Emerging evidence positions TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domain) as a master checkpoint integrator that coordinately regulates CD8+ T-cell exhaustion, NK-cell dysfunction, and Treg-mediated suppression. Dual blockade of PD-1 and TIGIT represents a mechanistically rational strategy to dismantle this immunosuppressive fortress. This review synthesizes current understanding of the gynecologic TME architecture, delineates the molecular and cellular basis for TIGIT/PD-1 synergy, critically evaluates ongoing clinical translation efforts, and proposes an integrative framework leveraging spatial transcriptomics, single-cell resolution immunoprofiling, and patient-derived experimental models to accelerate biomarker-driven therapeutic development. Full article

Cancer progression is closely associated with dysregulation of apoptosis, enabling malignant cells to evade programmed cell death and develop resistance to therapy. Among the key regulators of this process, the tumor suppressor protein p53 and the Bcl-2 family of proteins play central and interconnected roles in controlling cell survival and mitochondrial integrity. In recent years, naturally occurring flavonoids have attracted considerable attention as potential modulators of these pathways due to their diverse biological activities and relatively low toxicity. This review provides a focused and integrative overview of how different subclasses of flavonoids modulate the p53–Bcl-2 signaling axis to regulate apoptosis in cancer cells. Particular emphasis is placed on the mechanistic interplay between p53 stabilization, transcriptional regulation of apoptotic targets, mitochondrial outer membrane permeabilization, and caspase activation. In contrast to previous general reviews on flavonoids and cancer, this work provides an integrated overview of evidence across multiple flavonoid subclasses and experimental cancer models, highlighting both shared and pathway-specific apoptotic responses. Experimental findings from in vitro and in vivo studies are discussed, including the effects of quercetin, kaempferol, myricetin, epigallocatechin gallate, and related compounds on cell-cycle arrest, oxidative stress, mitochondrial dysfunction, and intrinsic apoptotic signaling. Furthermore, the review examines the relationship between flavonoid chemical structure and biological activity, with particular attention to bioavailability, metabolic transformation, and strategies aimed at improving therapeutic efficacy, including structural modification and nanocarrier-based delivery systems. Despite promising preclinical findings, significant translational challenges remain, including poor pharmacokinetic properties, variability among experimental models, and limited clinical validation. Overall, flavonoids represent a promising class of bioactive compounds capable of targeting apoptosis through modulation of the p53–Bcl-2 network, and a deeper mechanistic understanding of their activity may support the development of novel targeted and combination anticancer therapies. Full article

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immature myeloid cell populations with potent immunosuppressive activity. MDSCs accumulate during states of chronic inflammation in response to inflammatory cytokine signaling that triggers emergency myelopoiesis in the bone marrow. In rheumatoid arthritis and experimental models of inflammatory arthritis, MDSCs were initially thought to serve as a regulatory checkpoint that limits excessive inflammation. However, subsequent studies have shown that these cells can either alleviate or worsen arthritis depending on immunophenotype, disease timing, microenvironment, cytokines/chemokines, and transcriptional states. Taken together, the seemingly paradoxical roles of MDSCs in inflammatory arthritis likely reflect a highly plastic and context-dependent myeloid continuum. This review examines current knowledge of MDSCs in inflammatory arthritis, highlighting the conditions that direct their functional diversity and the factors that determine whether they alleviate or exacerbate disease. We also discuss emerging therapeutic strategies and emerging concepts to better understand these immune cell populations in the context of inflammatory arthritis. Full article

Chronic infection with the hepatitis C virus (HCV) is the most significant risk factor for the development of hepatocellular carcinoma (HCC). It has been shown that the progression of HCV-related liver disease is mediated by both viral and host-specific factors. The HCV replication cycle is a host-dependent process that relies on intracellular signalling pathways within target cells. Thus, intracellular signal transduction plays a pivotal role in the modification of interactions between the host and HCV. These pathways are key regulators of liver diseases, including cirrhosis and HCC. In addition, HCV induces epigenetic modifications in the host genome that inhibit the expression of various tumour-suppressor genes. Some of these changes persist even after successful antiviral treatment and represent a continued risk for HCC development. Despite significant progress in the management of chronic HCV infection, this challenge remains unresolved. In this narrative review, we summarise the mechanisms of HCV-induced disease progression, focusing on the host immune response, the regulatory roles of viral and cellular proteins, and viral survival strategies during chronic infection. We also discuss HCV-induced epigenetic alterations that contribute to hepatocarcinogenesis both during infection and after viral clearance. These insights are important for identifying novel, reliable molecular biomarkers for patient surveillance and for designing new therapeutic approaches. Full article

TP53 is the most frequently altered tumor-suppressor gene in human cancer, yet efforts to therapeutically target p53 have yielded limited and inconsistent clinical success. We argue that this gap reflects not a lack of druggable biology, but an oversimplified conceptual framework that treats p53 as a binary wild-type versus mutant entity. Here, we synthesize emerging evidence supporting a model in which p53 operates across a spectrum of functional states defined by mutation class, allelic burden, isoform composition, aggregation propensity, post-translational regulation, and cellular context. These states shape distinct biological outputs, including transcriptional activity, dominant-negative and gain-of-function effects, immune modulation, and checkpoint dependency, which collectively determine therapeutic vulnerability. We review current strategies targeting the p53 pathway, including mutant p53 reactivation, targeted degradation, anti-aggregation approaches, immune-directed therapies, restoration of wild-type pathway activity, gene replacement, and synthetic lethal targeting of DNA damage response dependencies. Clinical and preclinical evidence highlights key limitations of each approach, including stoichiometric constraints, mutation specificity, context-dependent efficacy, and adaptive resistance. Notably, emerging evidence from preclinical and correlative clinical studies suggests that therapeutic outcomes may be more closely associated with p53 functional state than with TP53 mutation status alone. We further emphasize the emerging roles of p53 isoforms and the tumor immune microenvironment as critical modifiers of p53 activity and determinants of treatment response. Collectively, these insights support a paradigm shift toward mechanism-matched, biomarker-stratified strategies that align therapeutic modality with the operative p53 network. Future progress will depend on integrating multi-parameter diagnostics with rational combination therapies to fully exploit p53 as a central vulnerability in cancer. Full article

Background/Objectives: As important post-transcriptional and epigenetic regulators of gene expression, miRNAs play a pivotal role in modulating host–virus interactions. While prior reviews have addressed either direct miRNA–HIV genome interactions or miRNA-mediated immune modulation in isolation, the integrated dual functionality of these molecules has not been systematically characterized. This review aimed to comprehensively explore how miRNAs that target the HIV-1 genome simultaneously modulate key innate and adaptive host immune signaling pathways. The conceptual novelty of this study is determined not by the identification of previously unknown miRNA-target gene pairs, but by the systemic integration of two regulatory levels (direct inhibition of the viral genome and modulation of the host cell immune signaling pathways) within a unified analytical framework. Such an integrated approach reveals a proviral regulatory network that remains non-obvious when each of these levels is examined separately. Methods: A narrative review was conducted using PubMed, Scopus, Web of Science, and Google Scholar (all years through 2025). In Stage 1, publications reporting experimentally confirmed interactions between host miRNAs and the HIV-1 genome were identified, yielding a curated set of 15 miRNAs. In Stage 2, target genes for each miRNA were retrieved from miRTarBase, TarBase (experimentally validated) and TargetScan 8.0 (in silico predicted). In Stage 3, target genes were manually mapped to key immune signaling pathways (TLR, NF-κB, JAK-STAT). In Stage 4, targeted literature searches were performed for each miRNA–target gene pair to identify direct experimental evidence of interaction. All stages were performed by two independent researchers, with discrepancies resolved by a third. Results: Fifteen host miRNAs with experimentally confirmed binding to the HIV-1 genome were identified, targeting viral genes including nef, pol, vpr, gag, env, vif, and the 3′-UTR. Thirteen of these miRNAs were found to regulate components of major immune pathways. miR-92a-3p, miR-29a/b-3p, miR-150-5p, and miR-125b-5p emerged as the most pleiotropic regulators, simultaneously suppressing TLR signaling (TLR3, TLR7, TLR8, MyD88, TRAF3/6, IRAK1/4), NF-κB components (REL, RELA, NFKB1), JAK-STAT effectors (STAT1–3, STAT5A/B, JAK2), and negative regulators of cytokine signaling (SOCS and PIAS family proteins). miR-133b and miR-196b-5p were found to selectively regulate SOCS/PIAS proteins without involvement in other analyzed pathways, suggesting potential for selective therapeutic targeting. Conclusions: The analyzed miRNAs exhibit functional dualism, acting as direct post-transcriptional suppressors of the HIV-1 genome while simultaneously functioning as epigenetic modulators of host immune signaling. These two modes of action are not independent but together form a conceptual framework of a self-reinforcing proviral regulatory network that, based on the synthesis of published evidence, is proposed to promote viral latency and immune evasion. The identified miRNAs represent promising, albeit complex, targets for novel therapeutic strategies aimed at eliminating latent HIV reservoirs. Full article

DNA methylation is a key mechanism in epigenetic regulation and plays a pivotal role in tumor initiation, progression, and therapeutic resistance. We begin by elucidating how the dysregulation of key DNA methylation enzymes in tumors drives concurrent global hypomethylation and cytosine-phosphate-guanine (CpG) island hypermethylation. This aberrant epigenetic landscape promotes tumorigenesis through silencing tumor suppressor genes and triggering abnormal activation of oncogenic signaling pathways. Notably, DNA methylation is intimately linked to cellular pyroptosis. In particular, the hypermethylation-mediated silencing of pyroptosis effector genes represents a critical epigenetic mechanism underlying acquired drug resistance. Targeting DNA methylation with epigenetic drugs offers a novel strategy to resensitize tumors to chemotherapy, radiotherapy, and immunotherapy. Moreover, advances in nanomedicine have yielded smart platforms for the precise administration of epigenetic modulators and combination therapies. These platforms enable a coordinated “epigenetic priming-pyroptosis execution” strategy, which holds promises for reversing therapeutic resistance and remodeling the tumor immune microenvironment. By integrating DNA methylation regulation, pyroptosis mechanisms, and nano-targeted strategies, this review aims to provide a theoretical framework and novel perspectives for developing innovative, epigenetically driven anti-tumor therapies. Full article

Ferroptosis, an iron-dependent and lipid peroxidation-driven form of regulated cell death, has emerged as a “versatile player” in oncology. It exerts a dual, context-dependent role in cancer, acting as both a potent tumor suppressor and a facilitator of tumor progression and therapeutic resistance. This review systematically delineates the core molecular regulatory networks of ferroptosis, highlighting the intricate balance between its execution mechanisms—driven by polyunsaturated fatty acid (PUFA) oxidation, iron catalysis, and mitochondrial dysfunction—and the robust endogenous defense systems, including the GSH-GPX4, FSP1/DHODH-CoQ10, and GCH1-BH4 axes. We deeply explore the dichotomous nature of ferroptosis in tumorigenesis: while classical tumor suppressors like p53 and CDKN2A harness ferroptosis to halt tumor growth, cancer cells can hijack lipid metabolic reprogramming and specific enzymes (e.g., iPLA2β) to evade cell death and promote distant metastasis. Furthermore, we dissect the multidimensional crosstalk between ferroptosis and the tumor microenvironment (TME), emphasizing its bidirectional immunoregulatory effects. Although CD8+ T cell-derived IFN-γ can sensitize tumor cells to ferroptosis and amplify anti-tumor immunity, aberrant ferroptotic activation can paradoxically foster an immunosuppressive niche. Finally, we summarize the latest translational strategies using small-molecule inducers and synergistic combination therapies, emphasizing that biomarker-guided patient stratification remains the ultimate paradigm for overcoming resistance and realizing precision ferroptosis-targeted cancer therapy. Full article

Salt stress is one of the major abiotic stresses limiting the yield of agriculture production worldwide. Rice is an aquatic summer crop, while barley represents a drought winter crop. Both are classified as diploid sequenced crops within the Poaceae family, and are vital staples in the world. As a plant-specific transcriptional regulator, suppressor of gamma response (SOG) plays crucial roles in plant adaptation under abiotic stresses by repairing DNA damage pathway. However, little research has reported the function of SOGs in barley and rice. This study presents the first genome-wide identification and comparative analysis of the SOG gene family in barley and rice, two cereal crops with contrasting salt tolerance. A total of 97 HvSOGs and 74 OsSOGs were identified in the genome of barley and rice, which were divided into three subfamilies. There was significant variation between barley and rice in terms of gene structures, motif compositions, gene duplication, and cis-elements. Notably, rice may have suffered stronger purifying selection pressure than barley, whereas the proportion of SOGs with stress-related cis-elements was significantly higher in barley than in rice. The expression patterns of SOGs in barley and rice tissues under salt stress indicated that barley’s stronger salt tolerance was largely due to an energy-saving strategy in shoots. Moreover, homologous gene similarity comparison with sea barleygrass suggested that gene loss and possible functional divergence during evolution may contribute to salt sensitivity in rice. Functional validation of a differentially expressed OsSOG17 gene confirmed its positive regulatory role in salt tolerance. Our findings uncover an energy-saving strategy as a potential mechanism underlying differential salt tolerance, and functionally link a SOG gene to salt stress responses in rice. Full article

The tumor suppressor protein phosphatase 2A (PP2A) plays a crucial role in regulating oncogenic signaling. Its inactivation, specifically through inhibitory phosphorylation at Tyr307 mediated by SET and CIP2A, contributes to breast cancer (BC) progression. Modulation of these interactions represents a promising pharmacological strategy to restore PP2A function. We integrated computational approaches with experimental validation to analyse SET/CIP2A mechanisms and explore how PP2A reactivation suppresses tumor progression. Molecular docking and dynamics simulations showed that the SET inhibitor/FTY-720 forms stable hydrogen bond networks with SET, disrupting its interaction with PP2A. In contrast, CIP2A suppressor/erlotinib interacts with CIP2A through weaker hydrophobic and π-interactions. Protein–protein interaction analyses indicate reduced SET/CIP2A binding to PP2A upon treatment, supporting a structural basis for PP2A reactivation. Gene expression analyses revealed upregulation of PP2A, SET, CIP2A, and cytoskeletal markers in tumor and metastatic tissues. Studies on Triple Negative Breast Cancer (TNBC) cells showed that FTY-720 and erlotinib significantly reduce PP2A-Tyr307 phosphorylation, restoring its activity. Additionally, both compounds decreased c-Myc levels and inhibited Src/FAK/paxillin/PAK1 and ERK signaling, attenuating migratory and proliferative pathways. Our findings identify the SET/CIP2A–PP2A axis as a pharmacological target for the design of next-generation PP2A activators, highlighting the potential of inhibition as a therapeutic strategy to counteract TNBC progression. Full article

Chronic inflammation is a well-established risk factor for cancer progression. This review aims to determine how persistent inflammatory signaling reshapes the tissue microenvironment to favor tumor cell proliferation, survival, and progression. It also discusses the role of cytokines such as IL-6 and TGF-β, reactive oxygen species (ROS), and the transcription factors NF-κB and STAT3 in inflammation and in the tumor microenvironment. Sustained activation of these pathways promotes genomic instability, loss of tumor suppressor gene function, enhanced oncogene expression, and resistance to apoptosis, collectively facilitating malignant transformation and tumor development. The key novelty of this review lies in integrating these interconnected networks with new evidence to clarify how they drive cancer initiation and progression. Furthermore, we discuss the therapeutic potential of plant-derived bioactive compounds, with a particular emphasis on curcumin. Curcumin exhibits significant anti-inflammatory and anticancer effects through inhibition of NF-κB and STAT3 signaling and its downstream targets, thereby attenuating inflammation-driven tumorigenesis. However, its clinical application is limited by poor bioavailability. Finally, this review highlights current strategies to overcome these limitations and future directions for optimizing curcumin-based interventions in inflammation-associated diseases. Full article