The significance of cholesterol metabolism in cancer is a topic of renewed interest. Cholesterol is an essential factor for mammal cells, for it is not only involved in constituting the cell membrane, but also serves as a precursor to steroid hormones and bile acids. Numerous studies have provided increasing evidence of its high relevance to cancer progression. Targeting cholesterol metabolism by using cholesterol metabolism inhibitors has offered another therapeutic strategy for reversing drug resistance in tumors. Here, the regulatory process of cholesterol homeostasis under normal physiological conditions was introduced. Then, the mechanism by which cholesterol metabolism disorder caused gynecologic cancer development and therapy resistance was summarized. Finally, the therapeutic strategies targeting cholesterol metabolism were also discussed in this review.

We describe a 3-year-old patient with xeroderma pigmentosum (XP) and genetically confirmed XPA deficiency who presented with recurrent infections in early childhood. Immunological assessment revealed mild hypogammaglobulinemia with IgG2 and IgG3 subclass deficiencies, as well as impaired humoral immunity demonstrated by a reduced antibody response to repeated vaccinations against bacterial antigens. Flow cytometric analysis further showed an altered distribution of peripheral T helper (TH) cell subsets. In addition, we report a second case: a 33-year-old XP patient with ERCC4 deficiency who also exhibited IgG3 subclass deficiency and reduced response to booster vaccination. Functional studies revealed defective nucleotide excision repair (NER) following UV-C exposure, along with reduced B-cell activation capacity. These findings suggest a potential link between XP and immunoglobulin subclass deficiencies, indicating a susceptibility to infections in affected individuals. We therefore recommend that patients diagnosed with XP undergo comprehensive immunological evaluation to allow early detection of immunodeficiency and timely intervention, including booster vaccinations or prophylactic measures such as low-dose antibiotics or immunoglobulin replacement therapy when indicated.

Ferroptosis, a distinct form of regulated cell death, has attracted significant attention due to its critical role at the intersection of cellular metabolism, redox biology, and various human diseases. Macrophages play a key role in maintaining systemic iron balance, and their specific polarization states influence the regulation of ferroptotic processes. However, the therapeutic potential of ferroptosis in cancer is frequently limited by tumor-associated macrophages (TAMs), representing a significant challenge in applying immunotherapy to hematologic malignancies. Notably, inducing ferroptosis in macrophages themselves also holds therapeutic promise. This review synthesizes recent advances in macrophage ferroptosis research to clarify its role in disease pathogenesis. Importantly, we highlight the translational potential of the ferroptosis-TAM axis, suggesting that biomarker-guided modulation of this pathway, via novel nanocarriers or combination treatments, represents a paradigm-shifting strategy to overcome drug resistance and restore antitumor immunity in hematologic malignancies.

The upregulated expression of sterol regulatory element-binding protein 2 (SREBP2) has been observed in multiple types of malignant cancers. Ferroptosis is a form of cell death that is iron-dependent and driven by the accumulation of lipid peroxides. It has recently garnered considerable attention in Colorectal cancer (CRC) research. This study aims to investigate the role of SREBP2 in CRC ferroptosis resistance and the underlying molecular mechanisms.

SREBP2 expression was assessed in CRC. Functional assays were conducted in HT29 and RKO cells following SREBP2 knockdown or treatment with Betulin, the SREBP2 inhibitor. RNA-seq was used to screen the potential downstream targets of SREBP2. Mechanistically, ferroptosis-related markers and rescue assays revealed the relation between SREBP2 and CRC ferroptosis resistance mediated by GPX4 expression regulation. Furthermore, ChIP and luciferase assays were used to confirm the upstream that regulates SREBP2 expression. Finally, subcutaneous tumorigenesis model was employed to evaluate the therapeutic potential of targeting SREBP2 in CRC.

The upregulated SREBP2 expression in CRC drives the proliferation, migration, and invasion of CRC cells. Mechanistically, SREBP2 directly increases GPX4 transcription, thereby reducing the sensitivity of CRC to ferroptosis and facilitating CRC progression. Additionally, β-catenin was identified as an upstream regulator of SREBP2. Inhibition of SREBP2 sensitizes CRC cells to ferroptosis and suppresses tumor growth.

SREBP2 enhances ferroptosis resistance in CRC by upregulating GPX4, thereby contributing to tumor progression. Our findings highlight SREBP2 as a potential therapeutic target and provide a rationale for the development of SREBP2-targeted strategies in colorectal cancer.

Three nitro-substituted 2,3-dihydro-1H-perimidine derivatives (ortho, meta-, and para-nitrophenyl) were synthesised via a novel, additive-free ultrasonication-assisted method with high yields (up to 90%). Their structures were validated experimentally and supported by DFT calculations, which also provided insight into the reaction mechanism. Further molecular docking, integrated with MD simulation studies, against the identified EGFR mutants revealed strong binding affinities and stable interactions, especially for the ortho-nitro derivative. To validate these findings, we performed ADME and toxicity analyses that confirmed favourable drug-likeness and safety profiles. Potent anticancer activity consistent with computational predictions was confirmed by MTT assays on NCI-H460 cells. Cell cycle analysis showed that the compounds induced phase-specific arrest, contributing to reduced cell viability. Apoptosis was further validated by Annexin V flow cytometry and AO/EB fluorescence imaging, which revealed early and late apoptotic populations. Overall, the compounds demonstrated strong apoptotic and antiproliferative activity.

Traditional chemotherapeutic agents are indispensable in cancer treatment. However, their therapeutic efficacy is frequently constrained by associated toxicities and adverse effects. Among these adverse effects, cardiotoxicity has emerged as a major clinical concern due to the increasing incidence. Emerging evidence suggests that oxidative stress, programmed cell death pathways, oxidative stress, and inflammatory cascades predominantly mediate the pathogenesis of cardiotoxicity induced by chemotherapeutic agents. Current strategies for monitoring and prevention rely on potential biomarkers, including markers of myocardial injury (e.g., troponins and natriuretic peptides), inflammatory mediators (e.g., myeloperoxidase, interleukin-6, C-reactive protein, and tumor necrosis factor-alpha), and exosomal contents (e.g., microRNAs, proteins, and metabolites). Clinical trials and case reports have demonstrated that patients with chemotherapy-induced cardiotoxicity may benefit from therapeutic interventions such as angiotensin-converting enzyme inhibitors, dexrazoxane, and β-blockers. However, limitations associated with these potential biomarkers and therapeutic agents warrant further discussion because of the lack of solid evidence from large-scale, prospective clinical studies. In summary, further research is imperative to enhance the understanding, monitoring, and therapeutic management of cardiotoxicity associated with traditional chemotherapeutic agents.

Hepatocellular carcinoma (HCC) remains the most common primary liver cancer, with a high incidence and mortality rate. Remarkable progress has been made in cancer treatment in recent years; however, most patients with HCC still receive limited benefits from current treatment options. Therefore, there is an urgent need to explore novel and effective therapeutic strategies. Here, a novel combination therapy consisting of the calcineurin inhibitor cyclosporine A (CsA) and the flavone-naphthalimide-polyamine derivative 6c was identified. The combination of CsA and 6c inhibited cell viability and colony formation and induced GSDME-dependent pyroptosis. Mechanistically, RNA sequencing revealed that CsA and 6c synergistically activated the RIG-I-like receptor (RLR) signaling pathway. Moreover, the combination of CsA and 6c promoted RIG-I and MDA5 expression, TBK1 and IRF3 phosphorylation, and downstream target gene expression. RIG-I deletion attenuated the combination treatment-induced inhibition of cell growth, pyroptosis, and expression of IFN-stimulated genes (ISGs). Furthermore, combination treatment induced the downregulation of LDHA expression, leading to increased reactive oxygen species (ROS) generation. LDHA overexpression and ROS removal reversed the inhibitory effect of the combination treatment on HCC. Finally, combination of CsA and 6c suppressed tumor growth and pulmonary metastasis in vivo. Overall, our study suggests a novel synergistic treatment combination with a comprehensive mechanistic exploration, demonstrating that it is a promising strategy for HCC treatment via targeting RIG-I-like receptor signaling.

Breast cancer remains one of the leading causes of cancer-related mortality in women worldwide. Breast cancer stem cells (BCSCs) contribute to tumor initiation, metastasis, recurrence, and resistance to therapy. The Wnt signaling pathway is a major regulator of stemness properties and is associated with poor clinical outcomes. BIBR1532 is a selective telomerase inhibitor widely used in cancer research due to its ability to inhibit telomerase activity in tumor cells with minimal toxicity in normal tissues. This study aimed to investigate the effects of BIBR1532 on the Wnt signaling pathway in breast cancer cells and BCSCs.

Cytotoxicity of BIBR1532 was evaluated in MCF-7 breast cancer cells, MCF10A normal breast epithelial cells, and BCSCs using a 48-hour treatment. IC₅₀ values were calculated, and apoptosis induction was assessed. Changes in the expression of Wnt pathway-related genes following BIBR1532 treatment were analyzed using RT-qPCR.

The IC₅₀ values of BIBR1532 at 48 h were 35.29 µM for MCF-7, 28.16 µM for MCF10A, and 30.42 µM for the BCSC line. BIBR1532 markedly induced apoptosis in MCF-7 and BCSCs, whereas minimal apoptotic changes were observed in MCF10A cells. RT-qPCR analysis revealed significant modulation of genes in the Wnt signaling pathway: several oncogenic components were downregulated, while multiple tumor-suppressive genes were upregulated. Additionally, expression changes in less-studied Wnt-related genes may provide new insights for future breast cancer research.

BIBR1532 exerts selective cytotoxic and pro-apoptotic effects on breast cancer cells and BCSCs and modulates key components of the Wnt signaling pathway. These findings suggest that telomerase inhibition may influence stemness-related signaling in breast cancer.

To elucidate the dysregulation of ferroptosis in uveal melanoma (UM), a comprehensive understanding is required of the expression patterns of ferroptosis-related genes, their association with key driver mutations and clinicopathological features, and their prognostic significance in UM patients. We analyzed tumor tissues from 56 UM enucleated eyeballs using qRT-PCR, immunohistochemistry, and western blotting to quantify ferroptosis-associated genes (SLC7A11, SLC3A2, GPX4, TFR1, CISD1, ACSL4, LPCAT3). Serum glutathione (GSH), ferritin, and lipid peroxidation assays were performed. These data were integrated with clinicopathologic parameters, driver mutations, mitochondrial ultrastructure, mtDNA copy number, and clinical outcomes. Independent validation was performed using TCGA-UM data. SLC7A11 and GPX4 were significantly upregulated in BAP1-mutant tumors. High expression of these markers was associated with reduced metastasis-free and overall survival (p < 0.05). TFR1 was downregulated in BAP1-deficient tumors, and low TFR1 protein levels independently predicted poor prognosis (p < 0.01). Serum GSH was decreased in UM patients, despite upregulation of GSH-related genes, indicating systemic oxidative imbalance. Downregulation of CISD1, ACSL4, and LPCAT3 were linked to alteration in mitochondria morphology, elevated mtDNA content, and unfavorable prognosis. These findings indicate that ferroptosis dysregulation is a hallmark of aggressive UM. SLC7A11, GPX4, and TFR1 represent clinically relevant biomarkers and potential therapeutic targets.

In the past few years, several novel anticancer agents targeting protein kinases have been discovered expanding the available therapeutic arsenal. However, few new therapeutic approaches have been developed for the treatment of childhood cancer. To this end, we have been making efforts to contribute to this important field. Herein, we identified a series of new 4,6-disubstituted quinoline derivatives from our in-house quinoline chemical library that showed promising anti-proliferative activity against Ewing Sarcoma (ES). This interesting observation engaged us to further investigate these derivatives since this type of cancer is among the most common bone cancers in children. Evaluation of the quinoline derivatives against a panel of kinases demonstrated generally narrow selectivity profiles of this compound class. Interestingly, the main kinases that were inhibited belonged to the NAK family of kinases, in particular, the family member cyclin G-associated kinase (GAK) which was inhibited at nanomolar range in enzyme kinetic assays.