Search Results (2,000)

Background and Objectives: Endometriosis is associated with chronic inflammation, immune dysregulation, oestrogen-dependent growth, oxidative stress, altered steroid hormone metabolism, compromised epithelial barrier integrity, and the production of bioactive microbial metabolites. These interconnected alterations have been proposed to create, in principle, a permissive local microenvironment for malignant transformation. This narrative review examines whether endometriosis-associated dysregulation of the gut and reproductive tract microbiota may act as a hypothetical biological modulator linking these multi-axis changes to endometrial carcinogenesis, with attention to immunological, endocrine, metabolic, microbial–metabolite, oxidative, and barrier-related pathways. Material and Methods: We narratively integrated current evidence on gut and reproductive tract microbiota alterations relevant to endometrial homeostasis, with emphasis on the estrobolome, low-biomass uterine microbial communities, inflammatory and immune signaling, microbial metabolites, and pathways implicated in carcinogenesis. Results: Available data suggest that dysbiosis may influence endometrial carcinogenesis through interconnected endocrine, inflammatory, metabolic, and immune mechanisms. Attention has been given to loss of Lactobacillus dominance, enrichment of anaerobic and pro-inflammatory taxa, altered estrogen recirculation, progesterone resistance, Toll-like receptor activation, NF-κB/STAT3 signaling, COX-2/PGE2 activity, PI3K/AKT/mTOR pathway activation, oxidative stress, macrophage polarization, and impaired natural killer cell surveillance. These alterations may contribute to a permissive microenvironment characterized by persistent inflammation, defective immune control, and disrupted endometrial homeostasis. However, the current literature remains limited by small and heterogeneous cohorts, predominantly cross-sectional designs, contamination risk, and marked methodological variability, particularly in low-biomass uterine samples. Conclusions: Current evidence supports the view that microbiome dysregulation is a context-dependent biological modulator that intersects with endocrine, inflammatory, metabolic, immune, oxidative, and barrier-related pathways relevant to endometrial carcinogenesis. Microbiome dysbiosis should be regarded as a hypothetical contributory factor rather than as an established causal driver. Its near-term translational relevance appears greater for biomarker development and risk stratification than for immediate microbiome-directed therapy. Longitudinal, standardized, and functionally integrated studies are needed to clarify whether microbiome-associated signatures can be translated into clinically meaningful prevention and management strategies in endometrial cancer. Full article

Androgenetic alopecia (AGA) is the most common form of hair loss, characterized by the progressive miniaturization of hair follicles driven by dihydrotestosterone (DHT)-mediated androgen receptor signaling. Current pharmacotherapies remain limited in efficacy and are often associated with undesirable side effects. Pungenin, a phenolic glucoside isolated from Picea wilsonii Mast., was investigated for its therapeutic efficacy in DHT-induced AGA model mice in this study. In primary mouse hair follicle cells exposed to DHT, pungenin mitigated cellular injury, restored normal morphology and viability, and significantly reduced the expression of type II 5α-reductase (Srd5α2). Topical treatment with pungenin markedly accelerated hair regeneration, as demonstrated by histological analysis and serum biochemical measurements. Transcriptomic profiling combined with network pharmacology suggested that the protective effects of pungenin are associated with transcriptional regulation of the PI3K/AKT/FoxO/mTOR axis, identifying 25 putative therapeutic targets, with qPCR further confirming the altered expression of key genes within this network. Collectively, these findings demonstrate that pungenin protects hair follicles against DHT-induced injury through suppression of Srd5α2 and transcriptional modulation of the PI3K/AKT/mTOR signaling axis, supporting further preclinical evaluation of pungenin as a potential candidate for AGA management. Full article

Bergapten is a plant-derived linear furanocoumarin widely distributed in Rutaceae and Apiaceae species and increasingly recognized for its multifunctional anticancer potential. This review critically synthesizes current evidence on bergapten’s biosynthesis, physicochemical and pharmacokinetic properties, anti-inflammatory and antioxidant pharmacodynamics, and mechanistic antitumor activity, highlighting its translational relevance within pharmaceutical development. Preclinical studies across diverse malignancies demonstrate pleiotropic anticancer effects. Mechanistically, bergapten activates mitochondrial apoptosis via Bax/Bcl-2 modulation and caspase cascades, induces cell cycle arrest through p53–p21 signaling, and suppresses PI3K/Akt/mTOR and NF-κB pathways. Additional effects include PTEN-mediated autophagy induction, interference with metabolic reprogramming, reversal of multidrug resistance through ABC transporter modulation, and context-dependent photoactivated cytotoxicity. Beyond direct tumor cell targeting, bergapten attenuates pro-inflammatory mediators and regulates redox homeostasis through downregulation of NOX4-derived ROS and activation of Nrf2-driven antioxidant defenses, addressing the redox–inflammatory axis implicated in carcinogenesis. Despite promising mechanistic depth, clinical translation is limited by incomplete human pharmacokinetic data and poor aqueous solubility. Nanotechnology-enabled delivery systems and structural derivatives offer strategies to enhance bioavailability and therapeutic index. Overall, bergapten emerges as a systems-level phytochemical candidate warranting further translational investigation in oncology. Full article

Squamous cell carcinoma of the anal canal (SCAC) is a rare malignancy whose incidence has been steadily increasing worldwide. Persistent infection with high-risk human papillomavirus (HPV), particularly HPV16 and HPV18 genotypes, is the main etiological factor and plays a central role in tumor development. While combined chemoradiotherapy remains the standard treatment for localized disease and achieves high rates of tumor control, a considerable proportion of patients experience recurrence or present with advanced disease. For the latter, therapeutic options remain limited. Over the last decade, advances in genomic profiling have significantly expanded our understanding of SCAC biology. Recurrent alterations affecting the PI3K/AKT/mTOR pathway, especially PIK3CA mutations, have emerged as the most common molecular events, particularly in HPV-positive tumors. Additional alterations involve receptor tyrosine kinase signaling, chromatin remodeling genes, DNA damage response pathways, and components of the MAPK cascade. Moreover, HPV-positive and HPV-negative tumors display distinct molecular features with important prognostic implications. Immunotherapy has recently become an important component of treatment for advanced SCAC, although reliable predictive biomarkers are still lacking. This review summarizes the current evidence on the molecular landscape of SCAC, discusses emerging prognostic and predictive biomarkers, and highlights potential opportunities for the development of more personalized therapeutic strategies. Full article

Senotherapeutic agents targeting senescent cell (SnC) accumulation represent a promising frontier in aging research. These agents encompass senolytics that selectively eliminate accumulated SnCs and senomorphics that suppress the pathological persistence of the senescence-associated secretory phenotype (SASP). Concerns regarding off-target effects of synthetic senolytics have intensified interest in plant-derived alternatives that offer multitargeted mechanisms and favorable safety profiles. This scoping review was conducted following Joanna Briggs Institute guidelines and PRISMA-ScR, mapped preclinical evidence on plant-derived senotherapeutics published between 2015 and 2025 across PubMed, Scopus, Web of Science, Wiley Library and Google Scholar. Of 1355 identified articles, 111 studies met inclusion criteria. Most characterized compound classes included flavonoids, non-flavonoid polyphenols and stilbenes, terpenoids and alkaloids, and combination and complex plant extracts. Mechanistically, BCL-2/BCL-XL apoptosis, PI3K/AKT/mTOR and p53/p21/p16^INK4a modulation emerged as senolytic mechanisms, while NF-κB-mediated SASP suppression predominated among senomorphic agents. Ginkgetin-mediated cyclic GMP-AMP-synthase–stimulator of interferon genes (cGAS-STING) inhibition was identified as a mechanistically novel target within natural senotherapy. Metabolomics demonstrated dual utility in guiding compound discovery from complex plant matrices (e.g., phenolamides from Allium hookeri) and mechanistic validation by characterizing senescence-associated metabolic remodeling, including retinoic acid metabolism restoration, lipotoxic metabolites attenuation, tricarboxylic acid (TCA) cycle, and choline-betaine-TCA cascade regulation. However, challenges in pharmacokinetic optimization, methodological heterogeneity in senescence induction and biomarker panels persist. Plant-derived senotherapy characterized through metabolomics-guided pipelines provides a compelling foundation for their progression toward clinical validation and functional food applications as accessible interventions for healthy aging and age-related disease management. Full article

Background/Objectives: Sodium butyrate, a short-chain fatty acid produced by gut microbial fermentation of dietary fiber, has attracted increasing interest as a potential adjunctive therapy for ulcerative colitis (UC) because of its anti-inflammatory, barrier-protective, and immunomodulatory properties. This systematic review aimed to evaluate the current clinical and preclinical evidence regarding the efficacy and mechanisms of sodium butyrate in UC. Methods: A systematic review was conducted in accordance with the PRISMA 2020 guidelines and registered in PROSPERO (CRD420261437741). PubMed/MEDLINE, Scopus, Web of Science, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched from February through April 2026. Eligible clinical and experimental studies investigating oral or rectal administration of sodium butyrate in UC or experimental colitis were included. Risk of bias was assessed using RoB 2, ROBINS-I, or the SYRCLE tool according to study design. Results: Twenty-two studies were included, comprising ten clinical trials, one prospective observational study and eleven preclinical animal studies. In adults diagnosed with UC, oral sodium butyrate, particularly microencapsulated formulations, demonstrated encouraging effects as an adjunct to standard therapy by improving clinical remission rates, quality of life and reducing disease activity and inflammatory biomarkers. Evidence in pediatric inflammatory bowel disease remained inconsistent. Studies evaluating rectal sodium butyrate enemas reported variable clinical efficacy despite evidence of local biological activity. Preclinical studies consistently demonstrated reduced intestinal inflammation, improved epithelial barrier integrity, modulation of oxidative stress, favorable alterations of the gut microbiota, and regulation of several mechanistic pathways identified across individual preclinical studies, including PI3K/AKT/mTOR, WNT/ERK, ERK/STAT3, autophagy and ferroptosis. Conclusions: Current evidence suggests that sodium butyrate represents a promising adjunctive therapeutic strategy for UC, supported by consistent mechanistic findings and encouraging clinical results, particularly with oral formulations. However, the available clinical evidence remains heterogeneous, and larger, well-designed randomized controlled trials with standardized formulations and treatment protocols are required before its routine clinical implementation can be considered. Full article

Temporomandibular disorders (TMD) comprise a heterogeneous group of pain and dysfunction conditions involving the temporomandibular joint, masticatory muscles, and related structures. Although occlusal interference has long been discussed in relation to TMD, current evidence does not support an occlusion-centered etiological model for most patients. Within the contemporary biopsychosocial framework embodied by the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD), occlusal interference is better regarded as one of several potential peripheral biomechanical inputs that may interact with individual pain susceptibility, parafunctional loading, inflammatory status, and psychosocial factors. This review synthesizes evidence on how peripheral biomechanical and inflammatory inputs may engage masticatory muscle–nerve signaling, trigeminal nociceptor activation, and neurogenic inflammation. We discuss altered masticatory muscle activity, proprioceptive and nociceptive afferent signaling, neuropeptide release, neurovascular and mast cell–nerve interactions, and glial activation within trigeminal pain pathways. Molecular mechanisms, including TRP channel and P2X3 receptor activation, voltage-gated ion channel dysregulation, MAPK, PI3K/Akt/mTOR, cAMP/PKA/CREB signaling, and epigenetic regulation, are reviewed as candidate pathways linking peripheral input to pain-related plasticity. These mechanisms are further considered in relation to hyperalgesia, mechanical allodynia, pain memory, emotional and cognitive modulation, and sex-related differences in pain processing. Finally, we evaluate translational implications, including mechanism-oriented animal models, exploratory biomarkers, human-derived experimental systems, and mechanism-informed interventions, while emphasizing their current limitations. Overall, this review proposes a cautious mechanistic framework in which peripheral inputs may contribute to TMD-related pain amplification in selected contexts, but clinical translation requires validated phenotyping, longitudinal evidence, and integration with conservative, reversible, and patient-centered standard-of-care management. Full article

Ethanol (EtOH)-induced gastric ulcer (GU) is a common model used to investigate mechanisms of mucosal injury and repair. Omeprazole (OMP) is a conventional anti-ulcer drug that effectively suppresses gastric acid secretion, but its efficacy may be enhanced by combining it with bioactive phytochemicals derived from a Glycyrrhiza glabra L. (licorice; LIQ) extract that possess potent antioxidant and anti-inflammatory properties. The aim of the present study was to evaluate the gastroprotective effects of OMP, LIQ extract, and their combined treatment against EtOH-induced GU in rats, focusing on modulation of TLR4/NF-κB/NLRP3 signaling and PI3K/AKT/mTOR gene expression. The ethanolic extract of LIQ was chemically characterized by LC-ESI-QTOF-MS/MS, and molecular docking was performed to evaluate the potential binding interactions of its major constituents with H⁺/K⁺-ATPase and COX-2. Thirty male Wistar rats were randomly allocated into control, ulcer (ULC), OMP-treated, LIQ-treated, and combined treatment groups. GU was induced by absolute EtOH. Subsequently, gastric pH, stomach coefficient, oxidative stress, inflammatory mediators, and PI3K, AKT, and mTOR gene expression were assessed. Histopathological and immunohistochemical analyses of mucosal architecture and the expression of TNF-α, caspase-3, and PCNA were performed. Coadministration of OMP and LIQ demonstrated the greatest gastroprotective activity, marked by a significant increase in gastric pH, restoration of antioxidant status, and substantial reduction in ROS, TLR4, NF-κB, and NLRP3 levels. The combined therapy significantly upregulated the expression of PI3K, AKT, and mTOR genes in comparison to ULC. Histopathological and immunohistochemical findings further demonstrated preservation of gastric mucosal integrity, reduced inflammatory cell infiltration, and decreased TNF-α, caspase-3, and PCNA immunoreactivity, indicating attenuation of mucosal injury. In conclusion, LIQ extract enhanced the gastroprotective effect of OMP against EtOH-induced GU, supporting its potential as an adjunct to OMP. Further studies are warranted to confirm the underlying molecular mechanisms. Full article

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide despite substantial advances in surgery, chemotherapy, targeted therapies, and immunotherapy. The limited efficacy of current treatment strategies in advanced disease and the emergence of therapeutic resistance highlight the urgent need for novel adjunctive therapeutic approaches. Increasing evidence indicates that chronic stress and sustained activation of β-adrenergic signaling promote colorectal tumor initiation, progression, angiogenesis, metastatic dissemination, and immune evasion, thereby identifying this pathway as a potential therapeutic target. Drug repurposing has emerged as an attractive strategy for accelerating the development of new anticancer therapies by identifying novel applications for clinically approved drugs with well-established safety profiles. Among these, β-blockers have gained considerable attention because of their ability to inhibit β-adrenergic signaling and modulate multiple oncogenic pathways implicated in CRC progression. Although accumulating preclinical and observational clinical evidence suggests that β-blockers may possess anticancer potential, the underlying molecular mechanisms and their translational relevance have not yet been comprehensively integrated. This review provides a critical overview of the current evidence regarding the therapeutic potential of β-blockers in CRC by integrating findings from preclinical and clinical studies. Particular emphasis is placed on the regulation of key signaling pathways, including cAMP/PKA/CREB, PI3K/AKT/mTOR, and RAS/RAF/MEK/ERK, as well as on the effects of β-blockers on tumor cell proliferation, apoptosis, angiogenesis, epithelial–mesenchymal transition, metastasis, and modulation of the tumor microenvironment and antitumor immune responses. However, significant barriers limit the translation of these findings into routine clinical practice, including the limited representativeness of preclinical models, potential hemodynamic adverse effects, and the inherent limitations of observational studies. Importantly, owing to the lack of prospective randomized clinical trials, the current evidence remains insufficient to establish the clinical efficacy of β-blockers in CRC. Although β-blockers possess several characteristics that make them attractive candidates for drug repurposing, including a well-established safety profile, widespread availability, and low cost, further mechanistic studies, prospective randomized clinical trials, and biomarker-based patient stratification are essential to determine their clinical efficacy and define their role in personalized CRC therapy. Full article

Prostate cancer remains one of the most frequently diagnosed malignancies in men worldwide, and despite favorable outcomes for localized disease, progression to castration-resistant prostate cancer (CRPC) represents a major clinical challenge associated with poor prognosis. CRPC is characterized by disease progression despite castrate levels of circulating testosterone and is most commonly diagnosed in the metastatic setting. Although the introduction of second-generation androgen receptor-targeted therapies has improved survival, resistance inevitably emerges. This review overviews the most recent findings in the field of CRPC with particular emphasis on the current understanding of the biological mechanisms of hormone-resistant cancer as well as the evidence on treatment strategies. A comprehensive literature search was conducted across PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, focusing mainly on studies published between 2015 and 2025 that investigated molecular and cellular mechanisms of resistance to androgen deprivation therapy and androgen receptor (AR)-targeted treatments. Seventy-eight relevant articles were included in the final synthesis. The reviewed evidence highlights four major categories of resistance mechanisms. First, AR-dependent alterations remain predominant, including AR gene amplification, activating mutations, dysregulation of co-regulators, and expression of constitutively active AR splice variants such as androgen receptor variant 7 (AR-V7). Second, AR-independent or bypass pathways, most notably phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR), wingless-related integration site (WNT)/β-catenin, mitogen-activated protein kinase (MAPK), and glucocorticoid receptor signaling, enable tumor survival despite AR blockade. Third, lineage plasticity and transdifferentiation to neuroendocrine prostate cancer represent a distinct and increasingly recognized resistance mechanism driven by loss of tumor protein 53 (TP53) and retinoblastoma 1 (RB1) and epigenetic reprogramming. Finally, additional contributors, including intratumoral androgen synthesis, metabolic reprogramming, and tumor microenvironment interactions, further support disease progression. Together, these interconnected mechanisms underscore the biological complexity of CRPC and emphasize the need for biomarker-guided, combination-based therapeutic strategies to overcome resistance and improve patient outcomes. Full article

Milk-derived extracellular vesicles (EVs) transport microRNAs (miRNAs) that are unusually stable and have been proposed to survive digestion and modulate gene expression in the consumer, although their dietary bioavailability and physiological relevance remain debated. How the predicted regulatory potential of these miRNAs differs among the milks of different animals most relevant to human nutrition has not been systematically compared. Here, we performed an integrative in silico analysis of publicly available small-RNA sequencing data from 29 milk and milk-cell samples of human, cow, goat, and donkey origin. miRNAs were quantified against human (hsa) miRBase references—thereby restricting the analysis to evolutionarily conserved miRNAs with human orthologs—and their predicted effect on the human transcriptome was modeled by integrating predicted (mirDIP database) and experimentally supported (TarBase v9 database) miRNA–target interactions into a per-gene, per-species weighted targeting score. Because miRNAs act predominantly as repressors, this score is read as a prediction of which genes would be post-transcriptionally down-regulated in a recipient. miR-148a-3p dominated the exosomal spectrum of all four species (human, cow, goat, and donkey; ≈21.5% of pooled abundance), and the twenty most abundant miRNAs accounted for roughly three quarters of the signal. Of 4577 robustly targeted genes, a 1809-gene conserved “pan-milk” core showed the highest cross-species targeting and was enriched for transcriptional regulation, PI3K–Akt, MAPK, and TGF-β/SMAD signaling, autophagy and—strikingly—the components of the RNA-interference machinery itself. Species-restricted gene sets recapitulated biologically plausible programs, including a human-biased neuronal/axon-guidance and chromatin module, a donkey-biased transcriptional, epithelial, and immune (CD47) module, and a ruminant lipid/cholesterol and insulin–mTOR module. Across categories, we observed a reproducible confidence–exclusivity trade-off. We emphasize that these results are computational predictions that assume dietary miRNA uptake and do not constitute experimental validation. We provide the complete targetome as a hypothesis-generating resource to prioritize candidate genes, pathways, and milk types for future functional, nutritional, and epigenetic investigation. Across the 29 samples from the four species, miRNA composition segregated by species (silhouette width = 0.82, a cluster-separation measure ranging from −1 to 1, with values near 1 indicating well-separated groups) and the category structure exceeded a permutation null, indicating that the between-species signal is robust to differences in dataset origin and milk state. Full article

Inadequate supply of oxygen causing hypoxic cellular stress drives metabolic reprograming across diverse physiological conditions, including cancer. The activation of hypoxia-inducible factors (HIFs) to facilitate adaptation to low oxygen environments is well-characterized; however, post-transcriptional regulation by microRNAs (miRNAs) is poorly understood. Here, we investigated the mRNA and miRNA response in hypoxia-mediating reduced growth and cellular metabolism. Next-generation sequencing revealed the impact of hypoxia in cultured human hepatocellular carcinoma cells and identified over 400 mRNAs and 140 miRNAs that were differentially expressed. Hypoxia upregulated mRNA transcripts associated with glycolysis, DNA replication and the PI3K (phosphoinositide 3-kinase)-Akt pathway, which promote anaerobic metabolism for energy production, decreased cell proliferation and genomic instability, respectively. Upregulated miRNAs included miR-197-3p and miR-766-3p, targeting genes involved in lipid biosynthesis and metabolism. Downregulated miRNAs included miR-33a-5p and miR-15a-5p, targeting genes involved in glycolysis and lactate metabolism. Notably, miR-6834 emerged as a potential regulator of mechanistic target of rapamycin (mTOR) signaling and insulin-like growth factor binding protein-1 (IGFBP-1) signaling; miR-6834 overexpression altered 4E-BP1 phosphorylation levels and IGFBP-1 secretion. These findings provide critical insights into miRNA–mRNA regulation of metabolic adaptation and highlight miRNAs as potential targets for interventions with relevance to tumor biology and other hypoxia-associated conditions. Full article

Resistance to mTOR inhibition is mediated by multiple adaptive mechanisms, including feedback activation of the PI3K/AKT/mTOR pathway, autophagic adaptation, metabolic reprogramming, immune evasion, tumor heterogeneity, and microenvironmental crosstalk. Recent research has also elucidated the crucial role of RNA modifications, particularly m6A methylation, and the regulatory impact of non-coding RNAs in facilitating tumor adaptation to mTOR blockade. Accordingly, novel therapeutic approaches are emerging. The combination of PI3K/AKT/mTOR inhibitors with immune checkpoint blockades represents a promising strategy for overcoming therapeutic resistance. Additionally, next-generation mTOR inhibitors and synthetic lethality strategies are being tailored to target specific tumor profiles. Furthermore, advancements in multi-omics technologies and AI-powered predictive models are transforming personalized cancer treatment. This comprehensive review delves into the molecular intricacies of mTOR inhibitor resistance and explores innovative strategies aimed at enhancing therapeutic outcomes and improving patient responses. Full article

In this comparative study of 12 pigs (six Songlei black [SL] and six Duroc × Landrace × Yorkshire [DLY]), small RNA sequencing was performed on longissimus dorsi muscle samples to identify miRNAs associated with meat quality traits. A total of 343 known and 191 novel miRNAs were identified, including 21 differentially expressed miRNAs (DE-miRNAs) between breeds. Enrichment analysis showed that their target genes were enriched in the PI3K-Akt, MAPK, and calcium signaling pathways. Integration of miRNA and transcriptome datasets identified a regulatory network comprising five key miRNAs (ssc-miR-10383, ssc-miR-127, ssc-miR-370, ssc-miR-874, and a novel miRNA, novel_494) and 32 target genes annotated to autophagy, AMPK, mTOR, and FoxO signaling pathways. All five miRNAs were negatively correlated with IMF content (r = −0.77 to −0.95) and positively correlated with shear force (r = 0.62 to 0.76). This study provides the first miRNA expression profile of the longissimus dorsi muscle in SL and DLY pigs. These findings suggest that coordinated miRNA regulation may contribute to breed-specific differences in fat deposition and meat tenderness, providing candidate biomarkers for improving pork quality. Full article

Background/Objectives: Identifying molecular liabilities and understanding disease heterogeneity are prerequisites for advancing therapies in T-cell prolymphocytic leukemia (T-PLL), a rare T-cell malignancy with a poor prognosis. Methods: RNA-seq profiling of T-PLL samples (n = 10) and the normal counterpart (n = 5) allowed us to report gene expression and pathway alterations in malignant cells, revealing that non-coding, antisense and circular RNA expression is profoundly altered in T-PLL. Results: T-PLL displayed activation of several oncogenic pathways, particularly PI3K/AKT/mTOR and Wnt, suppression of healthy T-cell activities and cell death escape. Tumor suppressor lncRNAs (NEAT1, MIAT and LUCAT1) with reduced expression and upregulated oncogenic pro-proliferative lncRNAs (FIRRE, TERC, XIST and PVT1) were identified. CircRNAs ectopically expressed in T-PLL included circSEMA4B and circSATB1, linked to the Wnt pathway, circFIRRE and oncogenic circPVT1 and circFKBP5. Focusing on five genes with validated recurrent oncogenic variants (STAT5B, JAK3, ATM, KMT2C, and ARID1A), we investigated genotype/phenotype relations. A multiple predictor linear model suggested potential links between driver variants and alterations in gene and circRNA expression, including association between STAT5B mutations and LTF upregulation, JAK3 lesions and increased PLXNA4 expression along with CCR4 suppression. Conclusions: Our transcriptomic profiling and genotype–phenotype association analysis identified specific genes, non-coding RNAs, pathways and candidate genotype-associated transcriptional signatures that warrant further investigation as potential targets for the development of new therapeutic approaches for this rare and heterogeneous malignancy. Full article