Polyploid Giant Cancer Cells (PGCCs) are a malformed subpopulation of tumor. They play a crucial role in metastasis, recurrence, and therapy resistance. However, the inconsistent model systems and a lack of standardization have hindered mechanistic understanding and clinical translation. This review highlights the pluralistic research for clinical application by methodically analyzing various model systems used in PGCC research to fill the gap in the literature.

As of November 2025, scholarly literature gathered from Google Scholar, PubMed, and ScienceDirect focused on examining the development, characteristics, and functional involvement of PGCCs in cancer.

In vitro approaches, although limited in their physiological relevance, enable detailed mechanistic studies and facilitate the screening of drugs. Ex vivo tumor explants and organoids preserve patient-specific traits with translational potential, while in vivo models, such as Drosophila and mouse xenografts, provide insight into PGCC function in complex tissue environments. By mapping model capabilities against PGCC research priorities, we demonstrate that no single system comprehensively recapitulates PGCC biology, necessitating integrated, multi-model experimental strategies that we outline in this study. More specifically, integrating patient-derived organoids with lineage-traced xenografts and single-cell omics enables continuous tracking of PGCC development and functional diversity, facilitating mechanistic studies of metastasis, drug resistance, and identification of clinical biomarkers for patient stratification.

Considering the current lack of PGCC-targeted therapies, the convergence of model modification and the development of single-cell and imaging capabilities indicates significant progress toward therapeutically relevant findings. The ongoing development of these models is thus crucial for translating PGCC biology into predictive diagnoses and effective treatment methods.

Digestive system cancers (DSCs) constitute a significant number of cancer cases and are closely associated with modifiable risk factors.

This umbrella review synthesizes evidence from meta-analyses on the association between dietary polyphenol consumption and the risk of DSCs, addressing limitations in the literature and identifying optimal polyphenol types and doses.

Following Preferred Reporting Items for Systematic and Meta-Analyses (PRISMA) guidelines, a comprehensive literature search was conducted across PubMed, Scopus and Web of Science until April 2025, using specific keywords related to polyphenols and DSCs. Eligible studies included meta-analyses that examined polyphenol intake and DSC risk. The quality was assessed via the AMSTAR 2 and GRADE framework. Statistical analyses were performed using RStudio, employing random-effects models based on the heterogeneity metrics.

Data from six meta-analyses, encompassing 27 effect sizes, revealed a statistically significant 11% reduction in the risk of DSCs associated with polyphenol consumption (RR: 0.89; 95% CI: 0.85–0.93; I2: 63%). Subgroup analysis revealed significant risk reductions for specific polyphenol classes: flavonols (22%), quercetin (22%), anthocyanidins (16%), flavan-3-ols (12%) and isoflavones (9%). Publication bias was evident, but adjustments using the trim-and-fill method still indicated a 13% overall reduction in risk (RR: 0.87; 95% CI: 0.83–0.92; I2: 64%).

Our findings support the protective role of dietary polyphenols against DSCs, particularly flavonols and quercetin, suggesting that further investigations into the optimal intake levels and mechanisms of action are needed. These findings underscore the potential of dietary modification as a strategy for DSC prevention.

Alternative models are tools to replace and reduce the number of animals used in biomedical sciences, for either research or tests of industrial products. Several new alternative models have been developed in the most diverse fields. Their implementation has led to significant advances in the dermatological cosmetic industry, enabling chemical and molecular screening without animal use. However, limitations remain, particularly regarding tissue microenvironment complexity and systemic metabolic responses.

The objective of this viewpoint is to present the existing alternative models available for dermatological sciences, evaluate their applications and discuss their advantages and disadvantages, as well as the future perspectives for safe clinical translation.

In vitro and in silico approaches provide reliable platforms for toxicity, irritation, sensitization, and topical efficacy in cosmetic and dermatological research. Advanced systems, including human skin equivalents, bioprinted skin, and skin-on-a-chip platforms, enhance physiological relevance and mechanistic insight compared with two-dimensional cultures. However, limitations related to tissue complexity, systemic metabolic integration, standardization, and scalability still restrict their ability to fully replace in vivo models.

Therefore, it is expected that future developments in alternative technologies will further enable the reduction of animal model use, while still providing reliable and translatable knowledge applicable across scientific disciplines.

Lactate, generated through glycolysis, plays a dual role as both a metabolic substrate and a signalling molecule, influencing cellular functions in pathophysiological scenarios. Protein lactylation, a recently identified form of post-translational modification mediated by lactate, has garnered significant and increasing attention. Globally, hepatic disorders pose a significant public health burden, frequently involving disruptions in glucose metabolism and consequent lactate buildup.

This comprehensive review examines the discovery, regulatory mechanisms and pathogenic roles of lactylation in diverse liver disorders, while critically evaluating emerging lactylation-targeted therapeutics to guide future translational research.

Lactylation modifications play a pivotal role in various pathophysiological processes, including hepatic inflammation, liver fibrosis, ischaemic injury, tumour growth and metastasis.

Modulation of lactylation pathways, coupled with pharmacological control of lactate synthesis and shuttling, emerges as a strategic approach to liver disease therapeutics.

Bile acids (BAs) are crucial metabolic regulators and signaling molecules involved in lipid metabolism and ovarian function. They primarily affect follicular development, steroidogenesis, and oocyte maturation through systemic circulation and transporter-mediated uptake (e.g., NTCP, ASBT) rather than local ovarian synthesis. Increasing evidence indicates that BA dysregulation is associated with multiple reproductive pathologies.

This review is based on the authors’ own work and a comprehensive PubMed search of the literature to date on bile acids and female reproduction. PubMed was searched using the terms “bile acid AND ovary,” “bile acid AND oocyte,” and “bile acid AND reproduction.” Retrieved records were screened for relevance to ovarian physiology and pathology, including folliculogenesis, steroidogenesis, granulosa cell function, oocyte maturation, and reproductive disorders, and 51 articles were ultimately included in this review.

Studies show significant BA dysregulation in reproductive disorders. In polycystic ovary syndrome (PCOS), elevated glycochenodeoxycholic acid (GCDCA) and taurocholic acid (TCA) correlate with hyperandrogenemia. Excessive BAs can induce endoplasmic reticulum (ER) stress and granulosa cell apoptosis; for example, glycodeoxycholic acid (GDCA) promotes a BAX/BCL-2 imbalance and may accelerate follicular atresia. In contrast, protective BAs such as ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) alleviate ER stress and oxidative damage and may improve oocyte quality. Mechanistically, BAs regulate steroidogenic enzymes (e.g., StAR, CYP11A1) via the nuclear receptor FXR and modulate ovarian function through pathways including EGF–ERK1/2 and PERK–ATF4. Moreover, the gut–BA–ovary axis has emerged as a metabolic hub linking environmental factors to reproductive function, potentially contributing to PCOS pathogenesis and ovarian reserve decline through an integrated regulatory network.

BA-mediated signaling networks play important roles in ovarian physiology and reproductive disease. BAs and BA-related pathways may serve as novel biomarkers and therapeutic targets for reproductive disorders.

Circulating tumour cells (CTCs) are unique cells that originate from the main tumor site. They circulate in the bloodstream, and are implicated in metastasis, immune evasion and recurrence in various cancers. Associated biomarkers of importance for CTC detection include epithelial cell adhesion molecule (EpCAM), human epidermal growth factor receptor 2 (HER2), programmed death ligand-1 (PD-L1), cluster of differentiation 45 (CD45) and other cancer-specific biomolecules. Their roles as standalone biomarkers, have been thoroughly examined in CTC detection, isolation and targeting.

This review collates key findings on CTC characteristics and biomarker identification. The most recent CTC isolation and detection technologies are discussed, along with individual approaches based on inclusion and exclusion of cell-specific biomarkers. Emerging treatments integrating CTCs, including nanocarrier-mediated drug delivery, have been analyzed. We have discussed both the physical and research barriers in the current landscape.

Recent advances have determined that such biomarkers are more reliable when associated with secondary biomarkers, due to concerns regarding immune evasion and low sensitivity. The identification of these molecules has fast-tracked the development of several groundbreaking technologies.

The prognostic and predictive role of CTCs in various cancers revealed promising results. The development of integrative therapeutics can enhance patient survival and quality of life. These advancements depend on addressing key issues, such as molecular characterization and low abundance of CTCs.

The 22q11.2 Deletion Syndrome (22q11DS) is the most common chromosomal microdeletion disorder, characterised by a heterogeneous clinical spectrum including immunodeficiency, autoimmunity, and neuropsychiatric comorbidities. This systematic review critically appraises current evidence on autoimmunity in 22q11DS, fulfilling the need for an unbiased and comprehensive synthesis of the current literature.

An extensive search was conducted through PubMed, Web of Science, EMBASE, CINAHL, and the Cochrane Library using Boolean combinations of relevant keywords. Qualitative studies, abstracts, conference proceedings and non-English studies were excluded.

A total of 82 peer-reviewed studies published since 1968 were identified. We identified a total of 40 distinct autoimmune conditions involving multiple organ systems. Haematological disorders were most frequently cited, followed by autoimmune thyroid diseases and systemic autoimmune diseases. Less common conditions included coeliac disease, psoriasis, vitiligo, alopecia areata, Raynaud’s phenomenon, and vasculitis, while 19 diseases appeared only as single-case reports. Neuropsychiatric manifestations were addressed in 24 studies.

Our review confirms that autoimmunity is a complication of 22q11DS and highlights the need for epidemiological studies across organ-systems and inclusion of ethnically diverse populations. There was substantial variation in study designs, underscoring the need for more standardised approaches and larger sample sizes.

Blastocyst formation represents an essential requirement for subsequent implantation. Successful embryo implantation depends on adequate endometrial receptivity and appropriate embryo-maternal communication. Uterus-derived extracellular vesicles (EVs), as biological nanoscale particles carrying non-coding RNAs (nc-RNAs), DNAs, proteins and lipids, play a crucial role in promoting cellular interactions and regulating maternal-foetal dialogue.

This article systematically searched the PubMed database and used the following keyword combinations for literature screening : (exosome * OR ‘extracellular vesicle’) AND (uter OR blastocysti) AND (blastocyst OR embryo*).

The composition of uterus-derived EVs exhibits variation across different physiological periods and plays different roles. Compared with the proliferative phase, EVs during the peri-implantation period contain more molecules related to cell differentiation, cell cycle, cell migration and invasion, apoptosis and antioxidant activity. The EVs discovered from uterine fluid, primary human endometrial epithelial cells (EECs), endometrial stromal cell and so forth have been shown to be internalised by embryos and trophoblast cell. The cargoes carried by EVs, mainly miRNA and proteins, regulate embryonic development and invasion-related pathways or molecules, supporting blastocyst formation and implantation. Similarly, EVs collected from dysfunctional uterus have been proved to disrupt critical reproductive processes, impairing both embryo development and implantation potential.

This review summarises the multiple effects of uterus-derived EVs on successful embryo implantation, including the effects on pre-implantation embryo development and embryo implantation ability.

Hypoxia is a defining feature of the tumour microenvironment (TME) that drives aggressive tumour behaviour through coordinated adaptive responses. Hypoxia-inducible factors (HIFs), particularly HIF-1α, play a central role in orchestrating metabolic, immune and epigenetic reprogramming within tumours.

This review aims to elucidate the integrated roles of hypoxia in regulating angiogenesis, immune suppression, metabolic adaptation and epigenetic modifications, and to highlight their collective impact on tumour progression and therapeutic resistance.

A comprehensive review of current literature was conducted to examine the molecular and cellular mechanisms mediated by hypoxia and HIF signalling within the TME, with a focus on their interplay across angiogenic, immune, metabolic and epigenetic pathways.

HIF-1α promotes the expression of pro-angiogenic factors, including VEGF, ANGPT2 and CXCL12, leading to abnormal vascularisation and recruitment of immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells. This disorganised vasculature exacerbates hypoxia, reinforcing a cycle of immune evasion and metabolic stress. Hypoxia also upregulates immune checkpoint molecules (e.g., PD-L1, PD-1), contributing to T-cell exhaustion and impaired dendritic cell function. Concurrently, metabolic reprogramming—characterised by increased glycolysis, lactate accumulation and extracellular acidification—suppresses cytotoxic T cell and NK cell activity. Epigenetic regulators, including histone demethylases and DNA methyltransferases, sustain these adaptations through persistent transcriptional changes, referred to as hypoxic memory.

Hypoxia acts as a central organising force within the TME, coordinating angiogenic, immune, metabolic and epigenetic processes to promote tumour progression. Targeting HIF-driven pathways represents a promising therapeutic strategy to overcome immune resistance, enhance drug delivery and improve the efficacy of combination treatments, including immunotherapy and metabolic interventions. This review underscores the importance of integrated approaches to disrupt hypoxia-mediated tumour adaptation.

High altitude cerebral edema (HACE), a fatal terminal stage of acute mountain sickness (AMS), is triggered by rapid exposure to hypoxia at high altitudes. The pathophysiology of HACE is complex, involving multiple key processes including energy metabolism disorders, oxidative stress, blood-brain barrier (BBB) injury, and neuroinflammation, all of which interact to drive disease progression. Lactylation, a novel epigenetic regulatory mechanism discovered in 2019, provides a fresh perspective for HACE research.

This study integrates the latest research findings on the pathophysiology of HACE, lactate metabolism, and the role of lactylation in hypoxia-related diseases (such as cancer and ischemic-hypoxic diseases). It focuses on analyzing the potential molecular mechanisms of lactylation in HACE, including its regulation of the HIF-1α/NF-κB axis, inflammation, and metabolism, and discusses existing lactylation regulation strategies.

In HACE, hypoxia-driven glycolysis elevates lactate, promoting protein lactylation (e.g., NuRD complex in microglia, which is correlated with proinflammatory cytokines). Lactylation may regulate HIF-1α/NF-κB axis, inflammation, and metabolism in HACE pathogenesis. Currently, methods such as the inhibition of lactate dehydrogenase (LDH) /monocarboxylate transporters and the use of histone deacetylase inhibitors have been proven effective in regulating lactylation.

Lactylation is a key link connecting metabolic disorders and neuroinflammation in HACE. However, the dual role of lactate in neuroprotection and neuroinjury under hypoxic conditions still requires further exploration. Future research should focus on deciphering the molecular networks related to HACE and developing precise intervention strategies to provide new directions for HACE treatment.

Radiotherapy (RT) and immune checkpoint inhibitors (ICIs) have each transformed the treatment of malignant solid tumors (STs). Beyond direct tumor killing, RT remodels the tumor microenvironment (TME), promotes antigen release, and enhances immune activation. ICIs targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1) restore antitumor immunity by reversing T cell exhaustion. Increasing evidence indicates that RT can synergize with ICIs through mechanisms such as the abscopal effect, immunogenic cell death (ICD), and activation of the cyclic guanosine monophosphate–adenosine monophosphate (cGMP–AMP) synthase–stimulator of interferon genes (cGAS–STING) pathway.

This review summarizes current radiobiological, immunological, and clinical evidence regarding the synergistic effects of RT and ICIs in malignant STs, with a focus on underlying mechanisms, recent clinical advances, and translational challenges.

RT can enhance tumor immunogenicity, promote immune priming, and reshape the TME to improve the efficacy of ICIs. Synergy between RT and ICIs is associated with ICD induction, cGAS‒STING activation, enhanced systemic antitumor immunity, and modulation of immune cell infiltration and checkpoint signaling. Clinical studies across multiple STs have shown encouraging efficacy and manageable safety, although outcomes vary according to tumor type, disease stage, radiation schedule, and patient selection.

RT combined with ICIs is a promising therapeutic strategy for malignant STs. Further optimization of treatment regimens and biomarker-guided patient selection will be essential to maximize clinical benefit and enable more precise combination therapies.

Lifestyle changes and unhealthy eating habits have led to a sharp rise in obesity rates worldwide. Obesity is closely associated with a range of complications, including cognitive impairment and dementia. Accumulating evidence indicates that obesity negatively affects cognitive function and may increase the risk of neurodegenerative diseases. Conversely, cognitive dysfunction may further contribute to the development and progression of obesity. With growing attention in this field, obesity-related cognitive impairment has emerged as an important research focus at the intersection of metabolic and neurological disorders.

This article reviews the potential mechanisms underlying obesity-related cognitive impairment and summarizes emerging therapeutic strategies.

The development and progression of obesity-related cognitive impairment involve multiple mechanisms, including insulin resistance, systemic and central inflammation, immune dysregulation, microcirculatory alterations and changes in neurotransmitters and synaptic plasticity. Recent studies have focused on the adipose tissue-brain axis and the microbiota–gut–brain axis, in particular, the targeted effects of extracellular vesicles released from adipose tissue and microbiota on the brain.

This article systematically reviews the mechanisms underlying obesity-related cognitive impairment and presents novel therapeutic strategies.