BACKGROUND:The sphingolipid rheostat - the interconversion between pro-apoptotic ceramide (Cer) and pro-survival sphingosine-1-phosphate (S1P) - governs female reproductive homeostasis. This review integrates mechanistic evidence across the reproductive continuum to elucidate how compartmentalised disruptions of this axis drive divergent pathologies. METHODS:A systematic search up to 2026 across PubMed and Web of Science identified molecular mechanisms and translational models linking sphingolipid signalling to ovarian ageing, polycystic ovary syndrome (PCOS), endometriosis, adenomyosis and uterine fibroids. RESULTS:Pathological Cer accumulation drives mitochondrial outer membrane permeabilisation (MOMP) and cytochrome c release, accelerating follicular atresia in primary ovarian insufficiency (POI). Conversely, PCOS is associated with heterogeneous remodeling of follicular-fluid sphingolipids, compromising oocyte competence. Within uterine and peritoneal microenvironments, a hyper-activated S1P axis operating via S1PR1-3 networks acts as a core pathogenic engine. This axis exhibits a threshold-dependent dual nature: low thresholds promote homeostatic survival, whereas high thresholds drive M2 macrophage polarisation for immune evasion and cross-link with TGF-β/Smad and Activin A cascades to stimulate fibroblast-to-myofibroblast transdifferentiation (FMT) and extracellular matrix deposition in endometriosis and fibroids. Additionally, the SphK/S1P axis amplifies chronic pelvic pain by modulating nerve growth factor (NGF) and transient receptor potential vanilloid 4 channels. CONCLUSIONS:The sphingolipid axis constitutes a unifying molecular rheostat in reproductive medicine. Mapping these compartmentalised lipidomic signatures enables high-resolution diagnostics, while targeted sub-receptor antagonists and non-hormonal drug repurposing offer promising, fertility-preserving therapeutic frontiers. However, successfully translating these lipid-targeted interventions into clinical practice demands addressing key bottlenecks regarding systemic off-target toxicities and engineering advanced, tissue-specific delivery platforms.
Abstract Foetomaternal microchimerism establishes a lifelong reciprocal exchange of immune cells that shapes immunity in both mother and offspring. Foetal microchimeric cells (FMc) include CD34 + progenitors, CD8 + CTLs and Th2-polarized lymphocytes that integrate into maternal bone marrow, spleen and inflamed tissues, promoting peripheral tolerance via Treg (FOXP3 + CD4 + ) expansion, CTLA-4 upregulation and IL-10/TGF-β secretion, while inhibiting CD8 + cytotoxicity through clonal deletion and CXCR3 downregulation. Conversely, maternal microchimerism (MMc) transfers memory T cells, CD34 + HSCs and innate effectors (macrophages, NK cells) to the foetal thymus and lymphoid tissues, driving NIMA-specific Treg differentiation via CNS1-dependent Foxp3 induction and PD-L1 + DC suppression of Th1/Th17 responses. HLA class II incompatibility, complement (C3/C5a) and CCL2/CCR2 signalling coordinate this cellular crosstalk. Clinically, FMc enhances maternal tissue repair and cancer surveillance but increases autoimmune risk in scleroderma and PBC; MMc boosts newborn pathogen resistance and reduces GVHD in NIMA-matched HSCT. This review establishes microchimerism as a crucial regulator of intergenerational immunological homeostasis.
Colorectal cancer (CRC), a major global health burden, is the second leading cause of cancer deaths. This review examines the link between Helicobacter pylori infection and CRC, highlighting its role beyond gastric pathology. Affecting over half the world's population, H. pylori is associated with increased CRC risk through direct and indirect mechanisms. Direct pathways include toxins like CagA and VacA, which drive inflammation, and hypergastrinaemia, which promotes colorectal cell proliferation. Indirectly, H. pylori induces immune dysregulation, shifts to immune-evasive coccoid forms, survives intracellularly, releases oncogenic vesicles, disrupts autophagy, alters non-coding RNAs by dysregulating their expression profiles and contributes to gut microbiota dysbiosis. Additionally, we discuss the potential of probiotic interventions to counteract H. pylori's pathogenic effects by restoring gut microbial balance, reducing inflammation and modulating immunity by regulating cytokine and T-cell profiles. Future research should translate these molecular insights into clinical applications, including evaluating whether H. pylori eradication reduces CRC risk in high-risk populations and assessing the preventive potential of specific probiotic strains in controlled human trials.
BACKGROUND:Prostate cancer (PCa) exhibits profound metabolic reprogramming, including dysregulation of the urea cycle (UC), an emerging driver of tumour growth, therapy resistance, and immune modulation. In normal physiology, the UC detoxifies ammonia via urea production. In PCa cells, however, altered expression of UC enzymes such as argininosuccinate synthase 1 (ASS1), arginase (ARG) and ornithine decarboxylase (ODC1) reroutes metabolites towards other pathways, including polyamine and nucleotide synthesis. These changes enhance proliferation, facilitate metabolic plasticity and influence the tumour microenvironment. METHODS:This review summarises mechanistic insights into UC dysregulation in PCa, with emphasis on its interplay with the tricarboxylic acid (TCA) cycle, choline metabolism, and polyamine synthesis. RESULTS:We critically evaluate current therapeutic strategies such as arginine deprivation (PEGylated arginine deiminase, ADI-PEG 20, PEGylated recombinant human arginase 1, PEG-BCT-100), ODC1 inhibition (α-difluoromethylornithine, DFMO), and glutaminase blockade (CB-839) and discuss their integration with other therapies, including androgen deprivation. Furthermore, we explore the challenges and the usefulness of UC metabolites as diagnostic and prognostic biomarkers for early detection of PCa as well as for a follow-up of patients during therapy. CONCLUSIONS:We conclude that UC dysregulation represents a targetable metabolic vulnerability in PCa. However, successful translation will require combinatorial therapeutic approaches and rigorous validation of UC-based biomarkers in prospective clinical trials.
The β-galactoside-binding protein galectin-3 is currently a hotly pursued therapeutic target in cancer, inflammation and fibrosis-associated diseases due to its multi-mode actions and broad impact on the pathogenesis and progress of the diseases. Various natures of galectin-3 inhibitors have been developed and investigated, and several have shown promising results in early-phase clinical trials. All these galectin-3 antagonists were designed to target the canonical carbohydrate-binding site, the S-face, of the galectin-3 carbohydrate recognition domain (CRD). This review discussed the current galectin-3 antagonists and explored their modes of actions, focusing particularly on their targeting regions on galectin-3. It discussed the tri-modular structure of galectin-3 and the roles of different segments in galectin-3 actions. It proposed that, in addition to the canonical carbohydrate-binding sites on the S-face, the non-canonical carbohydrate-binding interface, the F-face of the galectin-3 CRD as well as its flexible N-terminal domain are also targetable in the design of galectin-3-targeted therapeutics. Given the high degree of structural similarities of CRDs among galectin family members but unique nature of galectin-3 N-terminus, antagonists developed against the N-terminal domain of galectin-3 can potentially offer greater target specificity by avoiding cross-reactivity with other galectin members. Antagonists that can interact with more than one segment of galectin-3, or a combination of antagonists against different galectin-3 segments, may potentially provide improved efficacy and therapeutic effectiveness for treatment of galectin-3-mediated pathologies and diseases.
BACKGROUND:Spontaneous intracerebral hemorrhage (sICH) remains associated with high mortality and long-term disability worldwide. Since the publication of the Surgical Trial in Intracerebral Haemorrhage (STICH) in 2005, numerous randomized controlled trials have evaluated surgical, pharmacological, and physiological interventions, yet most have not demonstrated consistent improvements in functional outcomes. METHODS:We critically reviewed major randomized controlled trials and influential studies of acute sICH treatment published over the past two decades, with particular attention to surgical strategies, physiological and pharmacological interventions, treatment timing, patient selection, and sex-related biological heterogeneity. RESULTS:Most conventional surgical and single-target medical interventions yielded neutral or modest results. Recent trials suggest that carefully selected surgery, early intervention, and bundled protocolized care may provide greater benefit. However, optimal treatment timing and sex-specific biological differences remain insufficiently investigated. CONCLUSIONS:Further progress in acute sICH treatment will require time-sensitive, mechanism-informed, anatomically tailored, and sex-aware multimodal treatment strategies rather than isolated interventions.
BACKGROUND:The receptor for advanced glycation end-products (RAGE) is a unique multi-ligand member of the immunoglobulin superfamily that exists in both membrane-bound and soluble forms. Under physiological conditions, RAGE expression is low in most tissues; however, it is markedly upregulated in response to tissue injury, inflammation or metabolic stress. Ligand-induced activation of RAGE initiates complex intracellular signalling cascades that regulate inflammation, extracellular matrix remodelling, cell proliferation, survival and migration. METHODS:While the contribution of RAGE to diabetes and chronic inflammatory diseases is well established, its role in gynaecological disorders remains insufficiently characterized. RESULTS:This comprehensive review summarizes current evidence on the involvement of RAGE in the pathogenesis of benign gynaecological disorders, such as endometriosis and polycystic ovary syndrome (PCOS), pregnancy-related complications and malignant neoplasms of the female reproductive tract. CONCLUSIONS:It also discusses emerging therapeutic strategies aimed at targeting the RAGE pathway, highlighting their potential translational relevance in gynaecological practice.
BACKGROUND:Lactosylceramides (LacCers) are glycosphingolipids that play essential roles in physiological and pathological processes across immune, endocrine, and neurological systems, with mechanistic studies demonstrating that LacCers modulate inflammatory signalling, oxidative stress responses, membrane microdomain organisation, and control aspects of mitochondrial function. Historically, LacCers were quantified predominantly as a total lipid subclass, limiting the ability to discern how individual species contribute to biological processes in clinical contexts. Recent advances in mass spectrometry based lipidomics now enable LacCer species to be resolved by acyl-chain length and saturation, offering far greater biochemical and clinical insights. METHODS:In this narrative review, we examine evidence from population based lipidomic studies describing how LacCer composition varies across healthy and diseased states. RESULTS:In metabolic and vascular disorders, multiple studies report elevations in specific short- and medium-chain LacCer species, whereas patterns involving longer-chain species appear more heterogeneous. Altered LacCer profiles have also been described in neurodegenerative disease, chronic kidney disease, and cancers, with species-level differences varying by disease-context, tissue type, and analytical platform. CONCLUSIONS:Our findings describe disease- and tissue-specific variations in LacCer acyl-chain composition, underscoring the value of species-level resolution for mechanistic understanding and informing the application of LacCer profiles in future biomarker and therapeutic studies.
Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder characterized by immune-mediated platelet destruction, impaired thrombopoiesis and a bleeding diathesis, with growing recognition of accompanying inflammatory and immunoregulatory disturbances. Despite the widespread use of corticosteroids, intravenous immunoglobulin (IVIG) and thrombopoietin receptor agonists (TPO-RAs), 30–50% of patients exhibit incomplete, unstable or transient platelet responses, underscoring a persistent unmet need for mechanism-informed therapeutic strategies. Current management paradigms remain largely focused on platelet count restoration rather than direct modulation of pathogenic platelet–immune crosstalk. Accumulating pre-clinical evidence, supported by limited clinical observations, implicates platelet glycoprotein VI (GPVI), a collagen receptor and immunothrombotic signalling hub, as a mechanistically relevant contributor to platelet hyperactivation, inflammatory amplification and aberrant platelet–leucocyte interactions in ITP. Experimental models indicate that GPVI-dependent signalling pathways can promote thromboinflammatory responses, facilitate immune cell engagement and influence platelet clearance dynamics, positioning GPVI as a plausible, albeit incompletely validated, therapeutic target. Emerging pre-clinical studies suggest that selective modulation of GPVI signalling may attenuate pathogenic platelet activation while preserving essential haemostatic function, thereby improving platelet survival and functional competence. This review integrates current insights into GPVI biology within the broader immunopathological landscape of ITP and evaluates innovative therapeutic concepts, including GPVI-targeted inhibitors deployed through nanocarrier systems, autologous platelet-mediated delivery and hydrogel-based protective platforms designed to enhance targeting precision and durability. We further discuss the rationale for combination strategies with established therapies and the potential utility of GPVI-linked biomarkers and platelet functional profiling to guide patient stratification. By reframing platelets as active immunoregulatory effectors rather than passive autoimmune targets, this review advances a mechanistic framework for next-generation, precision-oriented intervention in ITP. Although clinical validation remains limited, GPVI-centred strategies represent a rational and testable avenue for moving beyond symptomatic platelet augmentation towards disease-modifying immunothrombotic modulation.
Metastatic dissemination remains the leading cause of cancer-related mortality, driven not only by tumor-intrinsic factors but also by dynamic interactions within the tumor microenvironment (TME). Platelets and leukocytes orchestrate a systemic pro-metastatic network by shielding circulating tumor cells (CTCs), inducing neutrophil extracellular trap (NET) formation, and remodeling the extracellular matrix to prime pre-metastatic niches. This platelet-leukocyte crosstalk simultaneously promotes immune evasion, thromboinflammation, and metastatic seeding, creating a multi-cellular, temporally coordinated program that conventional anti-platelet and anti-inflammatory therapies inadequately target. Here, we propose a next-generation, multi-stimuli-responsive nanoparticle platform designed to disrupt these interconnected metastatic circuits. Engineered to respond to acidic pH in primary tumors and matrix metalloproteinases in pre-metastatic niches, these nanoparticles enable spatiotemporally controlled release of cytotoxic agents, anti-platelet drugs, and immune checkpoint inhibitors. Surface functionalization with anti-P-selectin further enhances specificity to tumor vasculature and facilitates platelet ‘hitchhiking’ for targeting CTCs. By simultaneously neutralizing platelet-leukocyte interactions, inhibiting NET-mediated scaffolds, and restoring anti-tumor immunity, this integrated strategy addresses multiple pro-metastatic mechanisms in a coordinated fashion. This work provides a conceptual and translational framework for precision anti-metastatic therapeutics, transforming the paradigm from single-pathway interventions to network-targeted strategies that disrupt tumor progression, CTC survival and metastatic niche formation. Our approach represents a critical step toward actionable, multi-modal interventions capable of preventing metastatic disease.
The escalating global prevalence of antibiotic-resistant Helicobacter pylori strains has undermined conventional eradication therapies, heightening the burden of associated conditions such as gastritis, peptic ulcers and gastric malignancies. Emerging non-antibiotic alternatives, including natural and synthetic compounds, probiotics and vaccine candidates, offer potential solutions to combat these infections effectively. Natural and synthetic compounds provide promising anti-H. pylori effects, primarily through bacterial membrane disruption, urease inhibition, virulence gene suppression and biofilm prevention. in vitro and in vivo studies support the robust activity of natural agents, while synthetic counterparts demonstrate potent bactericidal and anti-adherence capabilities, though rigorous clinical validation is still required. Probiotic strains enhance eradication rates when combined with antibiotics, reduce treatment-related adverse effects, modulate gut microbiota and attenuate gastric inflammation and carcinogenesis. Vaccine development encompasses whole-cell, subunit and DNA platforms targeting key virulence factors, showing immunogenicity and protective efficacy in preclinical models, yet is limited by variable clinical translation and insufficient large-scale trials. Despite promising advancements, challenges persist, including inconsistent efficacy and a need for more rigorous human studies. Future efforts should emphasize combinatorial therapies, refined delivery systems, and thorough safety evaluations to integrate these strategies into clinical practice, fostering sustainable management of H. pylori in a post-antibiotic era.
BACKGROUND: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. METHODS: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. RESULTS: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. CONCLUSION: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.
BACKGROUND: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. OBJECTIVE: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. METHODS: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. RESULTS: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. CONCLUSION: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.
Oxeiptosis is a reactive oxygen species (ROS)-dependent form of programmed cell death that plays a key role in cellular homeostasis and holds promise as a cancer therapy. This review explores its molecular mechanisms, emphasizing the KEAP1-PGAM5-AIFM1 signalling pathway and its reliance on ROS accumulation. Compared to other cell death pathways, oxeiptosis offers a distinct approach, especially for targeting cancer cells resistant to conventional therapies. The review evaluates emerging inducers, both synthetic and natural, that selectively trigger oxeiptosis in cancer cells. It also examines the potential synergy between oxeiptosis and ROS-generating chemotherapies, particularly in the oxidative tumour microenvironment. However, challenges remain, including identifying tumour-specific inducers, overcoming cancer cell resistance to oxidative stress and reducing off-target effects. The review concludes by highlighting the need for targeted delivery strategies and rigorous preclinical studies to translate oxeiptosis into effective cancer treatments. Overall, it underscores oxeiptosis as a promising avenue to address drug resistance and improve therapeutic outcomes in oncology.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with heterogeneous multi-organ manifestations and poorly understood pathogenesis. The variable therapeutic outcomes and potential for cross-indication treatments underscore the need to identify pivotal disease-driving signalling pathways for developing innovative and safer regimens. By categorizing the pathogenesis of SLE into three interconnected stages involving over-activated immune response, skewed cytokine homeostasis and impaired debris clearance, and by analysing public clinical data, this review posits that the Janus kinase-signal transducer and activator of transcription axis is a central driver of SLE pathogenesis. Accordingly, it explores the potential of cold atmospheric plasma to modulate this pathway for therapeutic benefit that requires further experimental and clinical validations.
