Persistent leukaemic stem cells (LSCs) in chronic myeloid leukaemia (CML) are insensitive to targeted tyrosine kinase inhibitors (TKIs). Identifying alternative molecular vulnerabilities may offer new therapeutic opportunities. This study aimed to identify active RAS/RAF signalling pathway components in persistent CML-LSCs using publicly available datasets to propose a novel drug combination that could synergise with TKI therapy.

EMBL-EBI Single Cell Expression Atlas and Stemformatics were used to analyse gene expression within the chosen signalling pathway using DESeq2 analysis in R Studio. Genes that showed statistically significant differences across three comparisons (CML vs. normal; post vs. pre TKI; post TKI vs. normal) were evaluated for gene dependency (Chronos scores), expression profiles, and inhibitor sensitivity using the DepMap platform, with a focus on CML cell lines. Candidate inhibitors were identified using DrugBank.

PPP2CA demonstrated broad essentiality with negative Chronos scores consistent with strong gene dependency. Its expression was consistently high, reinforcing its biological relevance in CML. LB-100 was found as a PP2A inhibitor under trial. Sensitivity analysis revealed LB-100 affected 548 cancer cell lines broadly.

PPP2CA represents a promising therapeutic vulnerability in CML, supported by both strong dependency and consistent expression in myeloid models, while BRAF showed limited relevance outside mutation-driven cancers. Variation in experimental platforms, sample representation, and data integration across public datasets is a recognised study limitation. Nonetheless, LB-100 may provide a novel therapeutic avenue in CML, provided further preclinical functional and clinical validation is performed in patient-derived samples to confirm translational applicability of the findings.

Breast cancer is the leading cause of cancer-related deaths in women, primarily due to distant metastasis. Metabolic reprogramming plays a critical role in tumor growth and spread, but the metabolic mechanisms underlying metastasis in breast cancer remain unclear. The primary objective of this study is to identify molecular targets mediating breast cancer progression and to evaluate whether targeting the metabolic reprogramming represents a potential therapeutic strategy.

To uncover key metabolic regulators involved in breast cancer progression, we analyzed high-throughput RNA sequencing data and identified Paired Like Homeodomain 1 (PITX1) as a frequently upregulated oncogene. Its expression was further validated by immunohistochemistry, quantitative PCR, and western blotting across various metastatic breast cancer tissues. The correlation between PITX1 expression and patient survival was also evaluated. Functional assays were conducted to explore the role of PITX1 in promoting breast cancer proliferation and metastasis. As this study is primarily based on mechanistic cellular and bioinformatic analyses rather than clinical intervention trials, traditional clinical effect size metrics are not directly applicable. However, we have now ensured that all major findings include quantitative effect measurements (e.g., fold changes, hazard ratios where applicable, correlation coefficients) together with corresponding statistical significance values to improve clarity and transparency.

Elevated PITX1 expression was significantly associated with poorer overall survival, distant metastasis-free survival, relapse-free survival, and post-progression survival in breast cancer patients. Silencing PITX1 significantly reduced breast cancer cell proliferation and suppressed glycolysis. Mechanistically, we found that PITX1 transcriptionally activates Phosphofructokinase platelet (PFKP), a key glycolytic enzyme, thereby enhancing glycolytic flux to promote tumor growth and metastatic capacity. Notably, isoliquiritigenin was identified as a small-molecule inhibitor that targets the PITX1-PFKP axis, downregulating glycolysis and consequently suppressing breast cancer progression.

Our findings uncover a novel oncogenic mechanism by which PITX1 promotes breast cancer progression and metastasis through glycolytic reprogramming. Targeting the PITX1-PFKP axis with isoliquiritigenin offers a promising therapeutic strategy for breast cancer treatment.

Granular cell tumor (GCT) of the neurohypophysis is a rare tumor originating from the posterior pituitary/infundibulum, classified as WHO grade I. Due to its imaging characteristics being highly similar to those of common sellar lesions, diagnosis typically relies on histopathology and immunohistochemistry.

A 43-year-old male presented with a one-month history of pulsatile temporal headaches without significant visual complaints. Endocrine tests showed reduced levels of growth hormone and prolactin. CT scan of the head and MRI of the sellar region revealed a well-defined solid mass in the sellar/suprasellar region (approximately 20×19×21 mm), compressing the optic chiasm and closely associated with the pituitary stalk. The patient underwent endoscopic transnasal transsphenoidal tumor resection. Intraoperatively, the tumor was soft but highly vascular, and adhered to the pituitary stalk, requiring meticulous hemostasis and en bloc removal. Postoperative MRI confirmed total resection. Histologically, the tumor consisted of polygonal to spindle-shaped cells with abundant eosinophilic granules in the cytoplasm. Immunohistochemistry showed positivity for TTF-1, S100, and CD68, with a Ki-67 index of approximately 5%, while SOX10 was negative, supporting the diagnosis of neurohypophyseal GCT.

We reviewed 88 published case reports to compare demographic characteristics, clinical presentations, endocrine abnormalities, treatment strategies, and recurrence rates.

Neurohypophyseal GCT should be included in the differential diagnosis of solid sellar/suprasellar masses associated with the pituitary stalk. Endoscopic transnasal transsphenoidal resection is effective, but the rich vascular supply and adhesion to the pituitary stalk can increase the surgical difficulty. Due to the potential for late recurrence, long-term follow-up is recommended.

The diagnosis of metabolic syndrome (MetS) in patients with polycystic ovary syndrome (PCOS) is complex. Various indicators are utilized to predict MetS in clinical practice. Nonetheless, there is ongoing debate regarding which indicator possesses a higher predictive value. This study examines the accuracy of the lipid accumulation product (LAP) in screening for MetS among patients with PCOS and compares it with other indicators.

A systematic literature search was conducted in PubMed, Embase, Web of Science, and the Cochrane Library to identify eligible studies. Outcomes were pooled using the mean difference, odds ratio, and diagnostic accuracy parameters, (including sensitivity, specificity, and the area under the summary receiver operating characteristic (AUROC) curve. Comparative analysis was performed using the Z-test.

A meta-analysis of 11 studies comprising 3720 participants revealed that LAP was significantly elevated in PCOS patients with MetS, with a pooled MD of 2.52 units (P<0.001). LAP demonstrated a strong association with MetS, yielding a pooled OR of 34.31 (P<0.001). For the detection of MetS, LAP exhibited a pooled sensitivity of 87% (95% CI: 79%-92%), specificity of 84% (95% CI: 79%-89%), and an AUROC of 0.92 (95% CI: 0.89-0.94). The AUROC of LAP was significantly superior to that of body mass index, waist circumference, triglyceride levels, and abdominal volume index (P<0.001).

LAP represent as a cost-effective, simple, and a better proxy indicator for screening MetS in the PCOS population.

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42025638798.

The interplay between JAK2 mutation, thrombosis, and the baseline clinical and hematologic profile of MPN remains poorly understood. This study aims to provide insight on the relationship between the clinical profile and hematologic findings, JAK2 V617F mutation, and the occurrence of thrombotic events in BCR-ABL1 negative MPNs.

We retrospectively analyzed 198 patients with BCR-ABL1-negative MPNs to assess associations between JAK2 V617F mutation status, hematologic parameters, clinical features, and thrombotic events.

Patients under 40 years old were associated with JAK2 V617F-negative MPN (p<0.05). In PV patients, cardiovascular comorbidities were associated with a 4.5-fold increased risk of thrombosis (OR 4.59; CI 1.57-13.43; p=0.005). Mutated-JAK2 V617F MPN was associated with lower platelets and higher WBC count, while thrombosis was associated with higher hemoglobin and hematocrit (p<0.01). However, we found no associations between JAK2 V617F mutation and thrombotic events across all MPN subtypes.

Cardiovascular comorbidity are an independent risk factor for thrombosis in PV. While JAK2 V617F mutation was associated with distinct hematologic profiles, it was not independently linked to thrombotic risk. These findings highlight the significance of clinical comorbidities and hematologic parameters in thrombotic event occurrences in MPN patients.

Monocytes are innate immune cells of the mononuclear phagocyte system, extensively involved in immune and inflammatory responses, and play a critical regulatory role in tumor development and progression. Different monocyte subsets can exert either pro-tumor or anti-tumor functions by modulating immune responses. Through the secretion of cytokines and chemokines, monocytes regulate immune activity, while tumor cells utilize these signaling pathways to influence monocyte polarization, inducing their transformation into immunosuppressive phenotypes. The origin, migration, polarization, and transformation of monocytes within the tumor microenvironment represent key research areas in current cancer immunotherapy. Precise regulation of monocyte function holds promise for developing novel strategies in tumor immunotherapy. Current approaches, such as monocyte-mediated vaccines and combination therapies with immune checkpoint inhibitors, have emerged as major research focuses in cancer immunotherapy. This review summarizes the mechanisms by which monocytes regulate antitumor immune responses and discusses recent advances in their therapeutic applications.

Hepatocellular carcinoma (HCC) is characterized by profound lipid metabolic rewiring that supports tumor growth, therapeutic resistance, and immune evasion. Among lipid metabolic regulators, acyl-CoA synthetase long-chain family member 4 (ACSL4) has emerged as a pivotal determinant of polyunsaturated fatty acid (PUFA) activation and membrane phospholipid remodeling. Accumulating evidence reveals a functional duality of ACSL4 in HCC. On one hand, ACSL4 amplifies lipogenic transcriptional programs, enhances fatty acid oxidation-mediated energy adaptation, and cooperates with oncogenic signaling networks to promote tumor proliferation and survival, particularly under nutrient stress such as transarterial chemoembolization (TACE). On the other hand, ACSL4-driven enrichment of PUFA-containing phospholipids establishes the biochemical foundation for ferroptosis, sensitizing tumor cells to sorafenib and CD8⁺ T cell-mediated oxidative killing. This apparent paradox can be reconciled by conceptualizing ACSL4 as a context-dependent metabolic switch. Its biological output is dynamically tuned by therapeutic modality, microenvironmental redox conditions, post-transcriptional regulation (e.g., miR-23a-3p and miR-145-5p), post-translational modification (e.g., SIAH2-mediated ubiquitination), and substrate flux partitioning. Through these multilayered regulatory mechanisms, ACSL4 integrates lipid remodeling with ferroptotic sensitivity and tumor-immune interactions within the tumor microenvironment. In this mini-review, we synthesize recent mechanistic and translational findings to propose a unifying framework for ACSL4 function in HCC. Understanding ACSL4 as a metabolic switch rather than a static oncogenic factor may enable rational design of ferroptosis-enhancing and immunometabolic therapeutic strategies and support biomarker-guided precision medicine in HCC.

Ewing's sarcoma (ES) is a malignant osseous neoplasm characterized by a dismal prognosis, particularly in its metastatic variant. The significance of disulfidptosis-a newly identified cell death mechanism induced by cystine metabolic imbalance and mitochondrial dysfunction-has yet to be investigated in ES. Thus, the aim of this study was to assess the prognostic significance of disulfidptosis-related genes (DRGs) in this disease.

We analyzed four GEO datasets to examine nine DRGs through differential expression, co-expression networks, and functional enrichment analyses. A predictive risk signature was developed using unsupervised clustering, Cox regression, and LASSO. Drug sensitivity was predicted using the GDSC database, and immune infiltration was quantified by ssGSEA. Single-cell RNA sequencing data was analyzed to explore DRGs distribution and functional heterogeneity. Molecular docking simulations were performed to evaluate interactions between DRGs and chemotherapeutic agents. Experimental validation of key DRGs was conducted in RD-ES cells using PCR and Western blotting, followed by functional studies of NDUFA11 via siRNA knockdown, assessing proliferation, migration, and invasion.

Eight of nine DRGs were dysregulated in ES tissues. A five-gene risk model (NDUFS1, LRPPRC, NDUFA11, OXSM, NUBPL) stratified patients into high- and low-risk groups with significantly different survival outcomes. The risk score was an independent prognostic indicator. Drug sensitivity analysis revealed enhanced response to microtubule inhibitors in the low-risk group. Single-cell analysis demonstrated predominant enrichment of these five DRGs in malignant ES cells. NDUFA11-high malignant cells exhibited distinct metabolic and signaling pathway enrichment and stronger intercellular communication with the tumor microenvironment. Molecular docking confirmed stable binding between DRGs proteins and chemotherapeutic compounds. Experimental validation confirmed dysregulation of all five DRGs at both RNA and protein levels in RD-ES cells. Functional studies revealed that NDUFA11 knockdown significantly suppressed ES cell proliferation, migration, and invasion.

This study provides the first prognostic signature connected to disulfidptosis for ES. Functional validation of NDUFA11 highlights its oncogenic role and potential as a therapeutic target. Single-cell analysis further elucidates the metabolic heterogeneity and microenvironmental interactions underlying ES progression.

Polycystic ovary syndrome (PCOS), a complex endocrine and metabolic disorder, involves significant dysregulation of the immune system. Natural killer (NK) cells, as key components of innate immunity, demonstrate notable phenotypic and functional alterations in women with PCOS. These changes include not only an elevated proportion in peripheral blood but also dynamic shifts within the local microenvironments of the ovary and endometrium. The increased level of peripheral NK cells correlates with a chronic low-grade inflammatory state, potentially serving as a predictive marker in infertile PCOS patients. Within the endometrium, uterine NK (uNK) cells exhibit reduced numbers and impaired function, accompanied by dysregulation of cytokine networks such as IL-15 and IL-18, which disrupts the immune equilibrium essential for embryo implantation. Abnormal NK cell function further involves alterations in killer immunoglobulin-like receptor (KIR) repertoires and dysregulated secretion of angiogenic factors, thereby compromising endometrial receptivity and vascular remodeling. Hyperandrogenemia modulates the distribution and activity of NK cells in reproductive tissues by influencing their surface activation markers, while insulin resistance promotes the generation of myeloid-feature NK (myNK) cell subsets via the IL-6/Stat3 signaling pathway, collectively exacerbating metabolic inflammation and reproductive dysfunction. Deciphering the role of NK cells in the immunometabolic interplay of PCOS reveals their position as a critical link between. May represent a potential cutoff requiring validation in larger cohorts reproductive impairment and metabolic disturbances, opening new avenues for targeted immunomodulatory interventions. Collectively, NK cells appear to present an important immunometabolic link between reproductive dysfunction and metabolic disturbance in PCOS, highlight their potential relevance as therapeutic targets.

Interleukin-15 (IL-15) is expressed in various cancers, including melanoma, where it exists in distinct membrane-associated isoforms. Primary melanoma cells predominantly express the non-cleavable transmembrane form (tmbIL-15), while metastatic cells also express a cleavable membrane-bound form (mbIL-15) complexed with IL-15Rα. As tmbIL-15 is capable of reverse signaling upon IL-15Rα engagement, we investigated how this signaling axis modulates melanoma cell behavior across tumor stages. Transcriptomic analysis of melanoma patients revealed that high IL-15 expression correlates with immune activation, inflammation and epithelial-to-mesenchymal transition (EMT), along with coordinated upregulation of IL-15 receptor subunits. Proteomic profiling of melanoma cell lines stimulated with soluble IL-15Rα (sIL-15Rα) uncovered distinct, stage-specific responses. Although several proteins were commonly deregulated across cell lines, most showed opposite regulation in primary versus metastatic models, indicating that tmbIL-15 reverse signaling triggers context-dependent programs influenced by tumor progression. A stringent cross-comparison identified five proteins (PSAP, MARCKS, eEF1A1, DDX39B, and RACK1) as consistently and differentially regulated across tumor stages. Further comparison with published NK cell co-culture and EMT cytokine stimulation datasets revealed a subset of shared effectors, notably PSAP, TPM3 isoform 2 and MARCKS, suggesting that IL-15Rα-induced tmbIL-15 signaling is part of the immune editing phenomenon eliciting pro-tumoral activities complementary to the EMT process. Among these, PSAP emerged as the most robustly and consistently modulated effector, upregulated in primary melanoma cells and downregulated in metastatic ones upon sIL-15Rα stimulation. Its expression correlated positively with CD8+ T cell infiltration and negatively with NK cell infiltration, with distinct transcriptomic programs associated with high PSAP expression in primary versus metastatic settings. Altogether, these findings identify PSAP as a stage-specific mediator of tmbIL-15 reverse signaling in melanoma, integrating immune and EMT-related cues with potential implications for tumor progression and microenvironmental remodeling.