The development of PI3K-targeted therapeutics has advanced significantly, yet molecular tools capable of simultaneous kinase inhibition and real-time visualization of drug distribution remain limited. Herein, we describe the rational design, synthesis, and biological evaluation of a novel fluorescent PI3K inhibitor (compound 1) that incorporates a 4-methylquinazoline pharmacophore conjugated to fluorescein isothiocyanate (FITC) through a piperazine linker. 1 demonstrated potent PI3K enzymatic inhibition and exhibited significant antiproliferative effects against HGC-27 and MCF-7 cancer cell lines. Mechanistic investigations revealed that 1 effectively suppresses DNA synthesis, triggers G0/G1 cell cycle arrest, and disrupts mitochondrial architecture. Fluorescence-based cellular and in vivo imaging studies demonstrated the compound's preferential cytoplasmic localization and tumor-targeting properties. This dual-function inhibitor not only advances PI3K-targeted drug discovery but also provides a valuable tool for real-time monitoring of drug distribution, representing a promising addition to the growing field of cancer theranostics.

PI3K and HDAC are concurrently upregulated in a variety of cancers, and simultaneous inhibition of PI3K and HDAC may synergistically inhibit tumor proliferation and induce apoptosis, providing a rationale for the study of dual-target PI3K/HDAC inhibitors. In this study, we rationally designed and synthesized a series of novel PI3K/HDAC dual-target inhibitors by combining the morpholino-triazine pharmacophore of PI3K inhibitor ZSTK474 with the hydrazide moiety of HDAC1-3 selective inhibitor 11h. Representative compound 31f possessed both PI3K (IC50 = 2.5-80.5 nM for PI3Kα, β, γ, and δ) and HDAC1-3 inhibitory activities (IC50 = 1.9-75.5 nM for HDAC1-3). 31f showed potent antiproliferative activity against a variety of tumor cell lines. Meanwhile, we designed and synthesized tool molecule 39a, a HDAC inhibitor structurally similar to 31f. In the mantle cell lymphoma Jeko-1 cell line, 31f showed significantly greater efficacy than the single inhibitors in inducing apoptosis. In conclusion, this study provided insights into the development of novel hydrazide-based dual HDAC/PI3K inhibitors.

Cardiotoxicity is a prevalent side effect linked to anthracyclines, a class of chemotherapy drugs, that frequently leads to the discontinuation of anthracycline-based treatments among cancer patients. Thus, there is a pressing need to mitigate and prevent these cardiotoxic effects. Mounting evidence suggests that Traditional Chinese Medicine may alleviate the toxic side effects of chemotherapy agents. For this reason, this study seeked to comprehensively assess the cardioprotective properties of the Qishen Huanwu capsule (QSHWC) against pirarubicin (THP)-induced cardiotoxicity in rat models and explore the underlying mechanisms.

The effects of QSHWC on anthracycline-induced myocyte damage was evaluated via CCK8 assay. Investigations conducted subsequently principally comprised network pharmacology methodology, Ultra-performance liquid chromatograph-hybrid quadrupole orbitrap high resolution mass spectrometer (UHPLC-Q-Orbitrap HRMS) and an anthracycline-induced cardiotoxicity (AIC) rat model to dig into the chemical constituents and potential therapeutic mechanisms of the QSHWC.

As evidently demonstrated by in-vitro studies, QSHWC not only effectively elevated the cell viability of H9c2 after anthracycline injury, but also downregulates NLRP3 expression and LDH release. As illustrated by in-vivo studies, medium and high doses of QSHWC improved the cardiac injury caused by pirarubicin, decreased myocardial injury scores, cTnT and NT-proBNP levels, and elevated the left ventricular ejection fraction (LVEF %). By conducting HPLC-Q-Exactive-MS analysis, we identified the major parts of the QSHWC. As suggested by network pharmacology and molecular docking analyses, QSHWC may exert cardioprotective protective effects by regulating multiple signaling pathways such as PI3K/AKT and NOD-like receptors. Last but not least, animal experiments confirmed that QSHWC can up-regulate phosphorylated PI3K and phosphorylated AKT in rat myocardial tissue, while down-regulating NLRP3 levels.

QSHWC alleviates anthracycline-induced cardiotoxicity by targeting cardiac pyroptosis through the PI3K/AKT pathway, while providing a multi-target therapeutic strategy.

Atherosclerosis (AS) is a primary contributor to cardiovascular disease. XinJia-LuHuang Granules (XLG), a formula used in traditional Chinese medicine (TCM), has been employed to treat AS. However, the underlying mechanism through which XLG exerts its effects remains unclear and warrants further investigation.

The purposes of this research are to assess the therapeutic effect of XLG on AS and to investigate its potential underlying procedures.

Network pharmacology was implemented to recognize XLG's active ingredients, along with their associated targets and pathways involved in the treatment of AS. Metabolomics was employed to detect changes in metabolites following XLG administration. Furthermore, a combined analysis of metabolomics and network pharmacology elucidated the key targets and pathways underlying the therapeutic effects of XLG in AS. The interactions between XLG's active ingredients and their specific targets were evaluated using molecular docking. In addition, an apolipoprotein E knockout (ApoE-/-) mouse model was used to simulate AS. Hematoxylin-Eosin (HE) staining and Oil Red O staining were utilized to assess the extent of pathological changes. An enzyme-linked immunosorbent assay (ELISA) was employed to measure inflammatory responses. The biochemical analyzer was applied to evaluate serum lipid levels in the mice. Immunofluorescence (IF) staining was conducted to measure the expression levels of key proteins in the sphingosine-1-phosphate receptor 1 (S1PR1)-activated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/endothelial nitric oxide synthase (eNOS) signaling pathway. In cell experiments, the viability of human umbilical vein endothelial cells (HUVECs) was detected using Cell Counting Kit-8 (CCK-8). Western blot (WB) analysis and ELISA were executed to measure the expression levels of proteins in the S1PR1-activated PI3K/Akt/eNOS signaling pathway both before and after the administration of specific inhibitors.

XLG contains 143 active ingredients and 309 potential targets, of which 193 are associated with AS. Metabolomic analysis revealed alterations in lipid substance levels. Combined with molecular docking analysis, it was observed that the principal active ingredients of XLG interact directly with these targets, potentially exerting anti-AS effects through the PI3K/Akt/eNOS signaling pathway. Animal experiments found that XLG reduced blood lipid levels and inflammatory cytokine content in AS mice. Additionally, the expression levels of PI3K, AKT, eNOS, and S1PR1 were significantly upregulated following XLG administration. Furthermore, XLG promoted the proliferation of HUVECs in response to lipopolysaccharide stimulation and improved vascular function through the S1PR1-activated PI3K/Akt/eNOS signaling pathway. Conversely, the therapeutic efficacy of XLG was diminished upon administration of an S1PR1 inhibitor.

Our research indicates that XLG may employ the S1PR1-activated PI3K/Akt/eNOS signaling pathway to produce its anti-AS actions. This research improves our understanding of the underlying mechanism by which XLG treats AS, providing a promising therapeutic approach for managing the condition.

Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality due to resistance, metastasis, and recurrence. Unlike conventional cytotoxic therapies, Xingxiao Pills (XXP), a classic traditional Chinese medicine formula, offers a complementary approach to treating LUAD, while its non-cytotoxic anti-cancer mechanisms remain unclear.

To investigate the effect and mechanism of XXP on LUAD progression and stemness via lipid metabolism regulation.

UHPLC-MS/MS was used to analyze the chemical constituents of XXP. The effects of XXP on LUAD cell proliferation, migration, invasion, and stemness were evaluated using CCK-8, Transwell, and tumor sphere assays. A LUAD xenograft model confirmed XXP's anti-tumor effects. Transcriptomics, metabolomics, ELISA, qRT-PCR, and Western blot were used to investigate the underlying mechanisms. Kaplan-Meier (KM) survival analysis and stemness index scores were performed for LUAD patients based on the TCGA dataset. Statistical analyses were performed using Student's t-test, ANOVA, and KM survival analysis (p< 0.05 considered significant).

XXP inhibits LUAD progression in mouse and cell models by targeting lipid metabolism reprogramming. It suppresses FA synthesis, elongation, oxidation, and glycerophospholipid (GPL) metabolism while upregulating arachidonic acid (AA) metabolism. Mechanistic studies revealed that XXP attenuates tumor stemness by inhibiting PLA2G4A (cPLA2), lowering AA release, and disrupting SMO/GLI1/SOX2 signaling, an effect also observed with the cPLA2 inhibitor AACOCF3. KM analysis showed that higher PLA2G4A expression correlated with a worse 5-year prognosis in LUAD (p = 0.0047). The low GPL/high AA group (consistent with XXP's metabolic pattern) had better survival (p = 0.0028) and a lower stemness index (p< 0.0001) than the high GPL/low AA unrelated group.

Xingxiao Pill modulates GPL and AA metabolism and downregulates the PLA2G4A (cPLA2)-AA/SMO/GLI1/SOX2 axis. Through this mechanism, XXP effectively inhibits tumor growth and stemness by targeting lipid metabolism.

Tyrosine kinase inhibitors (TKIs) are commonly used in cancer treatment, but their off-target effects can lead to serious cardiotoxicity. Our previous studies have revealed that upregulation of phosphoinositide 3-kinase (PI3K) confers considerable protection against calcium (Ca2+) disorders and cardiac dysfunction induced by sunitinib. However, the involvement of PI3K inhibition in the prevention of cardiomyocyte contraction induced by other TKIs remains unclear.

Herein, we selected three TKIs with different targets and mechanisms, namely, sunitinib, imatinib, and trametinib, and assessed their myocardial toxicity, PI3K activity, and Ca2+ regulation in AC16 cells and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).

All three TKIs induced AC16 cell damage and reduced PI3K expression. These drugs also caused hiPSC-CM injury, increased reactive oxygen species (ROS) release, induced cytoplasmic Ca2+ overload, and inhibited cell contraction. Phosphatidylinositol (3,4,5)-trisphosphate pretreatment and adenovirus-mediated p110α overexpression activated PI3K, prevented TKI-induced Ca2+ overload and ROS release, and reduced TKI-induced myocardial injury and contraction inhibition.

All three TKIs induced cardiotoxicity by inhibiting PI3K activity.

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are among the most common oncogenic alterations in various cancers, including pancreatic, colorectal, and non-small cell lung cancer (NSCLC). Targeting KRAS has long been considered a difficult challenge due to its high affinity for guanosine triphosphate (GTP) and the lack of a druggable binding site. However, recent advancements in small-molecule inhibitor design have led to the development of targeted therapies aimed at KRAS mutations, particularly the KRASG12C mutation. Inhibitors such as Sotorasib and Adagrasib have shown promise in preclinical and clinical studies by irreversibly binding to the mutant KRAS protein, locking it in an inactive state and disrupting downstream signaling pathways critical for tumor growth and survival. These inhibitors have demonstrated clinical efficacy in treating patients with KRASG12C-mutated cancers, leading to tumor regression, prolonged progression-free survival, and improved patient outcomes. This review discusses the synthetic strategies employed to develop these KRAS inhibitor and also examines the clinical application of these inhibitors, highlighting the challenges and successes encountered during clinical trials. Ultimately, KRAS inhibitors represent a breakthrough in cancer therapy, offering a promising new treatment option for patients with KRAS-driven tumors.

Phosphatidylinositol 3-kinase Class IIγ (PI3KC2γ) is a critical regulator of PI(3,4)P2 production on endosomal membranes, linking its activity to metabolic disorders such as diabetes, glycogen storage diseases, and hyperlipidemia. Despite its importance, selective inhibitors targeting PI3KC2γ remain underexplored. In this study, we developed novel scaffolds for PI3KC2γ inhibitors using structure-based design. A series of inhibitors were synthesized, among which compound 23 was identified as the most potent PI3KC2γ inhibitor reported to date. Functional assays confirmed that compound 23 effectively inhibits insulin-stimulated PI(3,4)P2 formation, blocks glucose-to-glycogen conversion, and reduces excessive liver glycogen accumulation by downregulating the Akt2-glycogen synthase pathway. This study highlights the therapeutic potential of PI3KC2γ inhibition in glycogen storage diseases and provides efficient tool molecules for further drug development.

KRAS mutation results in higher proliferation rates and miserable prognosis of cancers. Targeting the interaction between KRAS and PDE6D provided an alternative strategy to overcome KRAS-mutant pancreatic cancers. Gaudichaudione H (GH) is a prenylated caged xanthone isolated from Garcinia oligantha. In this work, GH was selected as a potential anti-cancer compound by MTT screening of twelve prenylated xanthonoids from G. oligantha. Further studies demonstrated that GH inhibited proliferation of a panel of cancer cell lines and induced pancreatic cancer cell apoptosis. GH suppressed xenograft tumor growth accompanied with decreased phosphorylation of ERK and AKT. Binding with PDEδ and thus interfering the KRAS-PDEδ interaction was verified as the possible mechanism of GH. These findings implicated GH as a promising candidate for the treatment of pancreatic cancers with KRAS mutation, provided novel insight into the underlying mechanisms of GH-induced anticancer effects.

Dietary interventions can influence tumor growth by restricting tumor-specific nutritional requirements, altering the nutrient availability in the tumor microenvironment, or enhancing the cytotoxicity of anticancer drugs. Metabolic reprogramming of tumor cells, as a significant hallmark of tumor progression, has a profound impact on immune regulation, severely hindering tumor eradication. Dietary interventions can modify tumor metabolic processes to some extent, thereby further improving the efficacy of tumor treatment. In this review, we emphasize the impact of dietary patterns on tumor progression. By exploring the metabolic differences of nutrients in normal cells versus cancer cells, we further clarify how dietary patterns influence cancer treatment. We also discuss the effects of dietary patterns on traditional treatments such as immunotherapy, chemotherapy, radiotherapy, and the gut microbiome, thereby underscoring the importance of precision nutrition.

Exploration of neoantigens holds the potential to be productive in immuno-oncotherapy. Among tumor-specific antigens, neoantigens result from genetic instability that gives rise to non-synonymous somatic mutations, highly specific to tumor cells. In addition to point mutations, gene rearrangements, indels leading to frameshifts, chromosomal translocations or inversions that may lead to fusion proteins, alternative mRNA splicing, and integration of genetic material of oncogenic viruses into the host genome provide consistent sources of neoantigens that are absent in healthy tissues. Out of these alterations, 2%-3% may generate T cell neoepitopes, possibly detectable by TCRs. Neoantigens are absent in healthy tissues and are thus at low risk of triggering autoimmunity. In addition, the host lymphocytes have not been rendered tolerant toward them and it is possible to induce immune responses against them. Here, we overview the two categories of neoantigens, i.e., private and shared, and their use in immuno-oncotherapy in selected pre-clinical and clinical studies. The vast majority of commonly occurring tumor-specific mutations are cancer causing and are permanently expressed by all malignant tumor cells, preventing the latter from escaping vaccine-induced anti-neoantigen immunity. The use of public neoantigens combined with efficient vaccine platforms can provide non-personalized "off-the-shelf" therapeutic vaccine candidates for broad-spectrum immunotherapy purposes.

The eukaryotic initiation factor 5A2 gene (EIF5A2) is a highly conserved and multifunctional gene that significantly influences various cellular processes, including translation elongation, RNA binding, ribosome binding, protein binding and post-translational modifications. Overexpression of EIF5A2 is frequently observed in multiple cancers, where it functions as an oncoprotein. Additionally, EIF5A2 is implicated in drug resistance through the regulation of various molecular pathways. In the review, we describe the structure and functions of EIF5A2 in normal cells and its role in tumorigenesis. We also elucidate the molecular mechanisms associated with EIF5A2 in the context of tumorigenesis and drug resistance. We propose that the biological roles of EIF5A2 in regulating diverse cellular processes and tumorigenesis are clinically significant and warrant further investigation.

Natural products have made significant contributions to the prevention and treatment of malignant tumors. However, natural products often suffer from low efficacy and potential toxicity. Therefore, modifying and optimizing lead compounds derived from natural products is a crucial strategy in drug development. In this study, we used matrine as an ideal lead compound and synthesized 27 matrine derivatives by incorporating indole structures with known antitumor activity. The antiproliferative effects of these derivatives were evaluated against human cancer cell lines (A549, HeLa, and Huh-7) and normal human liver cells (LO2). Compared to matrine, most of the derivatives exhibited superior antiproliferative activity. Notably, compound 9q showed significant antiproliferative activity against HeLa cells, with an IC50 value of 4.48 μM, demonstrating approximately 1500-fold greater potency than matrine (IC50 = 6756 μM). Further mechanistic studies revealed that compound 9q inhibited HeLa cell proliferation by modulating the expression of PI3K/AKT and Activating transcription factor 4 (ATF4) proteins. The upregulation of ATF4 promoted the expression of the key endoplasmic reticulum stress (ER stress) protein C/EBP homologous protein (CHOP). In the HeLa xenograft mouse model, compound 9q demonstrated significant anticancer efficacy. Therefore, compound 9q holds promise as a potential lead compound for the development of novel anticancer drugs.

This study evaluates the potential of oral rinse-derived and plasma circulating tumour DNA (ctDNA) in HPV-negative oral squamous cell carcinoma (OSCC), where early recurrence occurs in a significant proportion of patients, contributing to poor prognosis. Analysis of paired tissue, oral rinse, and plasma samples from 123 patients revealed ctDNA detection rates of 94.3% in oral rinse and 80.5% in plasma samples. Combined testing improved mutation detection sensitivity to 48.6%. A machine learning model integrating seven mutated genes (TP53, TERT, IKZF1, EP300, MYC, EGFR, PIK3CA) and clinical factors demonstrated robust prediction of recurrence (validation AUC: 0.854) and survival outcomes. Integration of pretreatment plasma ctDNA status further enhanced predictive performance. In longitudinal analysis, ctDNA detected recurrence approximately four months before clinical manifestation. These findings suggest that integrated ctDNA analysis offers improved mutation profiling and outcome prediction, potentially enabling earlier interventions in OSCC.

Urological cancers, including prostate, kidney, bladder, testicular, and penile cancers, pose a significant health challenge, particularly in their metastatic stages. Surgical interventions remain fundamental, but recent advancements in medical therapies like chemotherapy, immunotherapy, and targeted therapies have shown promise in improving patient outcomes.

This review aims to explore the current landscape of targeted therapies in urological cancers, focusing on the role of key signaling pathways such as phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), mechanistic (mammalian) target of rapamycin (mTOR), growth factor-related mechanisms, c-Mesenchymal-epithelial transition factor (c-Met)/ hepatocyte growth factor (HGF), programmed cell death protein 1 and its ligand programmed death-ligand 1 (PD-1/PD-L1), and steroid hormone receptor pathways in tumor progression and therapeutic resistance. Key scientific concepts of review Dysregulation of pathways like PI3K/Akt and mTOR contributes to tumorigenesis, metastasis, and resistance to treatment, underscoring their relevance as therapeutic targets. Tyrosine kinase inhibitors and immune checkpoint inhibitors have demonstrated efficacy but face challenges such as intrinsic resistance and treatment-related toxicities. Integrating insights from signaling pathway research with clinical practice holds potential for developing more effective treatment paradigms, enhancing the efficacy of targeted therapies, and improving survival rates for patients with urological cancers.

Erdheim-Chester disease (ECD) is a rare form of non-LCH characterized by excessive accumulation of histiocytes in various tissues, leading to significant morbidity. The estimated prevalence of ECD is low, with fewer than 1000 cases reported globally, yet it presents considerable clinical challenges due to its heterogeneous manifestations, which include bone pain, cardiovascular complications, and neurological symptoms. Traditional treatment approaches, primarily involving corticosteroids and chemotherapy, have limitations, including inconsistent responses and significant side effects. Recent advances in understanding the pathogenesis of ECD, particularly the role of the BRAF V600E mutation, have led to the exploration of novel therapeutic strategies, such as targeted BRAF inhibitors, MEK and mTOR inhibitors, and other immunotherapies, which offer promise in improving patient outcomes. The review further explores clinical manifestations, and radiographic features of Erdheim-Chester disease, and discusses treatment strategies, current clinical studies in the field of ECD. By integrating these aspects, this review aims to provide a thorough understanding of ECD and its evolving treatment landscape, ultimately contributing to improved patient outcomes.

Current risk assessment models for predicting ischemic stroke (IS) in patients with atrial fibrillation (AF) often fail to account for the effects of medications and the complex interactions between drugs, proteins, and diseases. We developed an interpretable deep learning model, the AF-Biological-IS-Path (ABioSPath), to predict one-year IS risk in AF patients by integrating drug-protein-disease pathways with real-world clinical data. Using a heterogeneous multilayer network, ABioSPath identifies mechanisms of drug actions and the propagation of comorbid diseases. By combining mechanistic pathways with patient-specific characteristics, the model provides individualized IS risk assessments and identifies potential molecular pathways involved. We utilized the electronic health record data from 7859 AF patients, collected between January 2008 and December 2009 across 43 hospitals in Hong Kong. ABioSPath outperformed baseline models in all evaluation metrics, achieving an AUROC of 0.7815 (95% CI: 0.7346-0.8283), a positive predictive value of 0.430, a negative predictive value of 0.870, a sensitivity of 0.500, a specificity of 0.885, an average precision of 0.409, and a Brier score of 0.195. Cohort-level analysis identified key proteins, such as CRP, REN, and PTGS2, within the most common pathways. Individual-level analysis further highlighted the importance of PIK3/Akt and cytokine and chemokine signaling pathways and identified IS risks associated with less-studied drugs like prochlorperazine maleate. ABioSPath offers a robust, data-driven approach for IS risk prediction, requiring only routinely collected clinical data without the need for costly biomarkers. Beyond IS, the model has potential applications in screening risks for other diseases, enhancing patient care, and providing insights for drug development.

Phosphorylated products of phosphatidylinositol (PI), named Diphosphoinositide (DPI) and triphosphoinositide (TPI) were identified long time ago and found to exhibit high turnover rates based on their rapid 32P-phosphate labeling. The PI kinase activities that were responsible for their production were subsequently identified and found to be associated with different organelle membranes, including the plasma membrane. These activities were then linked with a certain group of cell surface receptors that activated phospholipase C enzymes to hydrolyze PI and used calcium or cGMP as a second messenger. This visionary concept was introduced in the seminal BBA review written by Robert Michell, exactly 50 years ago. The enzymology and functional diversity of PI 4-phosphate (PI4P) (the term that has replaced DPI) has since underwent an expansion that could not have been foreseen. In this review I will attempt to revisit this expansion with some historical reflections celebrating the 50th anniversary of the Michell review.

Triple‑negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype of BC characterized by the absence of estrogen, progesterone and human EGFR2 receptors. This lack of receptors renders it unresponsive to standard targeted therapies. Despite advances made in understanding the molecular landscape of TNBC, its poor prognosis and high recurrence rates underscore the urgent need for innovative therapeutic approaches. This review explores the effects of key prognostic markers, such as Ki‑67, programmed cell death ligand 1, BRCA1/2 mutations, E‑cadherin loss and EGFR alterations. It also examines critical pathways, including the PI3K/AKT/mTOR and mutant p53 pathways, which are prerequisites for TNBC progression and therapy resistance, and discusses the therapeutic potential of directly targeting these key molecules and their associated signaling pathways. In addition, recent advances in targeted therapies were highlighted, such as immune checkpoint inhibitors, and the statuses of emerging strategies were presented, such as chimeric antigen receptor‑T cell therapy and small inhibitory RNA‑based treatments. Given the molecular heterogeneity of TNBC, the importance of precision medicine was also discussed and it was emphasized that this approach is becoming an increasingly critical aspect of personalized treatment strategies. Resistance to existing therapies presents a major challenge to the effective treatment of TNBC, and thus, the development of future therapeutic strategies requires technical innovations. By integrating these insights, this review aims to provide a comprehensive overview of current and future means of improving TNBC outcomes.

Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) share a complex and multifactorial relationship characterized by overlapping risk factors, systemic inflammation, and intertwined pathophysiological mechanisms, with atherosclerosis emerging as a central inflammatory process connecting COPD and CVD, driven by systemic inflammation, oxidative stress, and endothelial dysfunction. While systemic inflammation is recognized as a critical link between these conditions, the precise pathways through which inflammation arises remain under investigation. There is therefore a need for therapeutic strategies to mitigate cardiovascular risks in patients with COPD. Among the pathways contributing to this interplay, the phosphoinositide 3-kinase (PI3K) signaling pathway has gained significant attention. Dysregulated PI3K signaling contributes to inflammation, oxidative stress, and endothelial dysfunction, which are key drivers of both COPD and CVD. Consequently, PI3K inhibitors have emerged as a promising therapeutic approach to mitigate inflammation and oxidative damage, offering a targeted strategy to address the shared pathological mechanisms underlying these diseases. A comprehensive understanding of the role of PI3K signaling and its inhibitors could facilitate the development of novel interventions to reduce cardiovascular risk in patients with COPD.

The clinical management of lymphatic malformations presents challenges due to their rarity, variable presentation, and the potential for recurrence. Dissemination of the latest knowledge in lymphatic malformations is needed to streamline referral pathways and possibly improve patient outcomes. This paper provides a narrative review of the latest developments in aetiopathogenesis, diagnosis and management of lymphatic malformations. Multidisciplinary recommendations from the European Reference Network on Rare Multisystemic Vascular Diseases, Vascular Anomalies working group sets the basis for this review. A literature search was conducted to include the latest research based on authors' preferences. Understanding the aetiopathogenesis of lymphatic malformations is important, as new genetic insights can dictate management strategies. Advancements in diagnostics allow for better differentiation between malformation types and imaging of anatomical infiltrations, where treatment options differ and are more commonly multimodal. Further systematic studies are needed on larger study populations, such as prospective trials and meta-analyses, to improve evidence-based practice.

Since the introduction of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) as the first-line treatment for metastatic hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative (HR+/HER2-) breast cancer, there has been a significant expansion in the number of therapeutic options for subsequent lines of therapy. Many new agents are being studied, with potential for future regulatory approval. The increased number of therapeutic options raises questions about the optimal selection and sequencing of therapies for individual patients. These advances represent an important clinical challenge in this rapidly evolving field, given the introduction of new therapies targeting various pathways (alone or in combination) and new therapeutic classes being studied.

Recently approved targeted therapies have demonstrated improvements in progression free survival (PFS) for patients whose cancer harbors mutations in the PI3K/AKT pathway, ESR1, BRCA1/2, and/or PALB2. Data to support continuation of CDK4/6 inhibition after progression on a prior CDK4/6i remains mixed, though some studies suggest a subset of patients may benefit from this approach. Several agents with unique mechanisms of action have shown promise in data from early phase trials, and have the potential to enter the treatment lexicon in the coming years. Examples include CDK2- and CDK4-selective inhibitors, complete estrogen receptor antagonists (CERANs), proteolysis targeting chimeras (PROTACs), and next-generation PI3K pathway inhibitors. In this narrative review, we summarize the current and upcoming treatments for metastatic HR+/HER2- breast cancer after progression on a CDK4/6i plus ET, with a focus on the following: an overview of first-line regimens of CDK4/6i plus ET and observed mechanisms of resistance; currently approved second-line therapy options; and upcoming options currently under exploration in clinical trials. We focus primarily on new therapy classes that may offer therapeutic options beyond currently available treatments.

Prostate cancer (PCa) is the most common cancer in men and the leading cause of cancer death worldwide. Overactivation of PI3K signaling has been reported to be associated with PCa. TGX221 is an effective specific inhibitor of PI3K, but its clinical application is greatly limited due to its poor solubility. Herein, by using folic acid-PEG-cholesterol semi-succinate (FA-PEG-CHEMS) as the targeting component, we developed a folate receptor-targeted pH-sensitive liposomal delivery system loaded with TGX221 (FA-Lip-TGX221) that could realize effective delivery and controlled release of drugs in the tumor. The prepared liposomes exhibited a uniform particle size and high stability. In addition, FA-Lip-TGX221 could be effectively internalized by PC-3 cells due to its ability to target folate receptors, thereby accumulating in tumor tissues. Meanwhile, in vitro and in vivo experiments suggested that FA-Lip-TGX221 could activate the PERK-ATF4-CHOP signaling pathway by inhibiting PI3K/110β signaling in PCa, thus significantly promoting endoplasmic reticulum (ER) stress-mediated cancer cell death. In conclusion, FA-Lip-TGX221 is a promising nano-delivery vehicle for the treatment of PCa, and also provide valuable references for all tumors overexpressing folate receptors.

Pituitary adenoma (PA) is one of the most common intracranial tumors, and owing to its special biological morphology and behavior, there is currently no effective treatment. miRNAs play crucial roles as diagnostic indicators and targets for the treatment of numerous cancer types. The objective of this research was to explore how miR-29a-3p influences the development of PA. We collected 25 pairs of PA tissue and normal pituitary tissue, followed by the subcutaneous injection of 5 × 107 HP75 cells into the left axilla of nude mice, creating a heterotopic PA xenograft tumor model for experimental study. TtT/GF and HP75 cell proliferation and tumor growth in nude mice were assessed using CCK-8, Transwell, and immunohistochemistry tests. Western blotting, RT‒qPCR and RIP were used to detect the expression and interaction of related proteins and genes. The expression of miR-29a-3p was upregulated in PA. Knockdown of miR-29a-3p can inhibit the proliferation, invasion and migration of TtT/GF and HP75 cells and reduce the epithelial mesenchymal transformation (EMT) of these cells. Furthermore, reducing miR-29a-3p levels suppressed the expression of Ki-67 in the PA tissues of nude mice and slowed tumor growth. From a mechanistic standpoint, miR-29a-3p can target COL6A6 and PTEN. Knockdown of miR-29a-3p inhibits the PI3K/Akt/CUX1 signaling pathway through simultaneously increasing COL6A6 and PTEN expression, thus inhibiting the proliferation, invasion, migration and EMT of PA cells and alleviating the progression of PA. Conversely, CUX1 can promote the expression of miR-29a-3p through a positive feedback loop and accelerate the development of PA. Our study suggests that downregulating the expression of miR-29a-3p may be a new target for the treatment of PA.

β-secretase 1 (BACE1), known for its role in amyloid-β production associated with Alzheimer's disease (AD), has also been suggested to be elevated in patients with Type 2 diabetes mellitus (T2DM). Notably, BACE1 could cleave the insulin receptor (InsR), leading to reduced InsR levels, which may impair insulin signaling and contribute to insulin resistance. Presently, we observed decreased InsR levels and impaired glucose disposal in the livers of mice with systemic overexpression of BACE1 (HUBC mice). This suggests that elevated BACE1 could contribute to insulin resistance by shedding membrane InsR. Additionally, mice fed a high-fat diet (HFD), a well-established model of T2DM, displayed increased BACE1 levels and decreased InsR. To further investigate whether inhibiting BACE1 could enhance insulin sensitivity and alleviate symptoms of diabetes, we treated HFD mice with the BACE1 inhibitor Elenbecestat. Remarkably, the administration of Elenbecestat restored InsR levels and improved their downstream signaling pathways, leading to increased insulin sensitivity and enhanced glucose tolerance. In summary, our findings suggest that inhibiting BACE1 can restore InsR expression and improve insulin-signaling sensitivity, ultimately resulting in enhanced diabetic phenotypes.

To assess the diagnostic utility of exome sequencing (ES) in macrocephalic fetuses.

Fetuses with macrocephaly (head circumference (HC) ≥ +2 SD) and negative chromosomal microarray results were included, who had available trio-ES data. Molecular diagnoses were systematically analyzed. Subgroup analyses were performed on the ES diagnostic yield based on gestational age, HC Z-scores, associated anomalies, and growth parameters.

Molecular diagnoses were established in 34 out of 87 macrocephalic fetuses (39.1%) through trio-ES. These diagnoses revealed that the variants predominantly affect key signaling pathways, including mTOR, RASopathies and Sotos syndrome. The detection rate was significantly higher in non-isolated compared to isolated macrocephaly cases (65.0%, 26/40 vs. 17.0%, 8/47; p < 0.001). The most frequent anomalies associated with genetic diagnoses included micromelia (100.0%, 14/14), megalencephaly (100.0%, 2/2), and ventriculomegaly (60.0%, 6/10). Subgroup analysis identified higher diagnostic yields in fetuses diagnosed before 32 gestational weeks, with HC Z-scores ≥ +3 SD, micromelia, and absence of large-for-gestational-age (LGA).

Exome sequencing significantly enhances the detection of monogenic disorders in macrocephalic fetuses compared with CMA, irrespective of isolated or non-isolated cases. These clinical features and phenotypes are essential for assessing monogenic disorders and for prenatal counseling and evaluations of macrocephalic fetuses.

Accurate characterization of cellular states is the foundation for precise prediction of drug sensitivity in cancer cell lines, which in turn is fundamental to realizing precision oncology. However, current deep learning approaches have limitations in characterizing cellular states. They rely solely on isolated genetic markers, overlooking the complex regulatory networks and cellular mechanisms that underlie drug responses. To address this limitation, this work proposes DeepCCDS, a Deep learning framework for Cancer Cell Drug Sensitivity prediction through Characterizing Cancer Driver Signals. DeepCCDS incorporates a prior knowledge network to characterize cancer driver signals, building upon the self-supervised neural network framework. The signals can reflect key mechanisms influencing cancer cell development and drug response, enhancing the model's predictive performance and interpretability. DeepCCDS has demonstrated superior performance in predicting drug sensitivity compared to previous state-of-the-art approaches across multiple datasets. Benefiting from integrating prior knowledge, DeepCCDS exhibits powerful feature representation capabilities and interpretability. Based on these feature representations, we have identified embedding features that could potentially be used for drug screening in new indications. Further, this work demonstrates the applicability of DeepCCDS on solid tumor samples from The Cancer Genome Atlas. This work believes integrating DeepCCDS into clinical decision-making processes can potentially improve the selection of personalized treatment strategies for cancer patients.

The PI3K/mTOR signaling pathway is often disrupted in human cancers, with PI3Kα being one of the most mutated kinases. There has been considerable interest in developing small-molecule inhibitors aimed at blocking the mutant PI3Kα-driven phosphatidylinositol 3-kinase (PI3K) signaling pathway as a potential treatment for cancer. In this study, we describe our effort to identify a compound, phenylacetamide-1H-imidazol-5-one (KIM-161), from our in-house oncogenic kinase-targeting inhibitors. KIM-161 showed excellent anti-proliferative activities at sub-nanomolar concentrations, primarily against mutant PI3Kα breast cancer cell lines, when compared with wild-type PI3Kα breast cancer cell lines, producing both dose- and time-dependent effects with an IC50 range of 1.42 - 0.064 µM. Next, we observed that KIM-161 was able to induce ROS production by modulating breast cancer metabolism, suggesting its broad effects on mutant PI3Kα regulated downstream pathways. We also computationally analyzed the binding interactions between KIM-161 and PI3K-alpha (PDB ID: 8EXL). Molecular docking showed that KIM-161 had a docking score of -7.44 Kcal/mol, compared to the reference compound, which had a docking score of -7.67 Kcal/mol. Moreover, molecular dynamics simulation studies demonstrated that the PI3Ka-KIM-161 complex remained stable throughout the 100 ns simulation, when compared to the PI3Ka complex with the co-crystallized inhibitor. These findings present KIM-161 as a promising lead, providing valuable insights into treatment approaches and resistance mechanisms associated with PI3K inhibitors in specific PIK3CA-mutant cancer subtypes.

Gliomas represent the most prevalent primary neoplasm in the adult central nervous system. Despite advancements in therapeutic modalities, such as surgical intervention, radiotherapy, chemotherapy, and tumor treatment, the 5-year survival rate of glioma patients remains low. Therefore, there is an urgent need to develop additional treatment methods. Recent studies have suggested that FAM111B is involved in DNA repair, cell cycle regulation, and apoptosis. FAM111B mutations and overexpression are related to cancer.

We found that FAM111B was significantly overexpressed in glioma tissues compared to the adjacent tissues by analyzing data from the TCGA_GBM&LGG and CGGA databases. Moreover, overexpression of FAM111B was associated with shorter overall survival, and disease-specific survival and tended to increase with disease stage progression. Cellular experiments confirmed these results. These results suggest that overexpression of FAM111B promotes the proliferation, migration, and invasion of glioma cells, whereas the knockdown of FAM111B inhibits these activities. We also found that FAM111B regulated glioma cell proliferation, migration, and invasion via the PI3K/AKT pathway.

FAM111B is capable of enhancing the proliferation, invasion, and migration capabilities of glioma cells and promotes the malignant progression of glioma via the PI3K/Akt signaling pathway.

This is the first study to demonstrate that FAM111B plays a crucial role in the proliferation, migration, and invasion of glioma cells. The malignant phenotype of FAM111B has also been shown to be closely associated with the PI3K/AKT pathway. FAM111B may be a predictive biomarker and a potential therapeutic target for gliomas.

Temozolomide (TMZ) chemoresistance is a major challenge in the management of glioblastoma (GBM). Marine-derived fungal metabolites are a significant source of potential chemotherapeutic candidates. This study aimed to investigate the cytotoxic effect of MHO7 (6-epi-ophiobolin G) on GBM cells. MHO7 inhibited GBM cell proliferation and promoted apoptosis, accompanied by a reduction in Akt activity and membrane phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3) content. We verified that MHO7 could react with phosphatidylethanolamine (PE), the second most abundant phospholipid in the plasma membrane, to form a covalent adduct. Pre-incubation with exogenous PE significantly alleviated the pro-apoptotic effect of MHO7, with a concomitant increase in Akt activity and membrane PIP2 and PIP3 content. Since binding to PIP3 is a key step in Akt activation, our results indicate that MHO7 can function as a novel Akt inhibitor. Additionally, MHO7 has a synergistic pro-apoptotic effect with TMZ, and TMZ-resistant GBM cells remain sensitive to MHO7. MHO7 had little cytotoxicity against normal neuronal cells. The anti-growth effect of MHO7 was also observed in an orthotopic glioma mice model. Therefore, MHO7 is a promising chemotherapeutic agent for GBM. This study also indicated that membrane lipid-targeted therapy may be a novel and effective strategy for tumor treatment.

Meningiomas are the most common primary intracranial tumors of adults. For meningiomas that progress or recur despite surgical resection and radiotherapy, additional treatment options are limited due to a lack of proven efficacy. Meningiomas show recurring molecular aberrations, which may serve as predictive markers for systemic pharmacotherapies with targeted drugs or immunotherapy, radiotherapy, or radioligand therapy. Here, we review the evidence for a predictive role of a wide range of molecular alterations and markers including NF2, AKT1, SMO, SMARCE1, PIK3CA, CDKN2A/B, CDK4/6, TERT, TRAF7, BAP1, KLF4,ARID1/2, SUFU, PD-L1, SSTR2A, PR/ER, mTOR, VEGF(R), PDGFR, as well as homologous recombination deficiency, genomic copy number variations, DNA methylation classes, and combined gene expression profiles. In our assessment based on the established ESMO ESCAT (European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets) evidence-level criteria, no molecular target reached ESCAT I ("ready for clinical use") classification, and only mTOR pathway activation and NF2 alterations reached ESCAT II ("investigational") classification, respectively. Our evaluations may guide targeted therapy selection in clinical practice and clinical trial efforts and highlight areas for which additional research is warranted.

Angioimmunoblastic T-cell lymphoma (AITL), a highly aggressive peripheral T-cell lymphoma (PTCL), carries a poor prognosis in elderly patients due to frequent relapse and limited salvage options after multiline therapy. We present the case of an 80-year-old woman with relapsed/refractory (R/R) AITL who relapsed after CHOP and exhibited resistance to the following sequential therapies: second-line chidamide plus COP and third-line chidamide with mitoxantrone hydrochloride liposome. Molecular analysis revealed DNMT3A and IDH2 mutations, reflecting disease complexity. Salvage therapy with linperlisib, a selective PI3Kδ inhibitor, combined with gemcitabine/oxaliplatin induced sustained partial remission, followed by linperlisib maintenance. The regimen demonstrated exceptional safety, with no grade ≥2 toxicities, even in this frail population. This case highlights the dual role of linperlisib as an effective and well-tolerated therapy for elderly R/R AITL patients who have exhausted prior lines. By precisely targeting PI3Kδ, our findings offer critical real-world evidence to address the unmet need for safe salvage strategies in this vulnerable population.

Atherosclerosis (AS) is a chronic inflammatory disease characterized by the gradual accumulation of plaques in arterial walls, with its pathogenesis remaining incompletely understood. Recent studies have highlighted that development of AS is closely associated with the aberrant activation of the NLRP3 inflammasome in the arteries. Inhibition of the NLRP3 inflammasome by natural products and formulae derived from Chinese herbal medicines (CHMs) has been shown to alleviate AS-associated pathologies. However, therapies that effectively and safely target the NLRP3 inflammasome remain limited. This review aims to summarize the key discoveries from recent studies on the effects of these natural products and formulae on the NLRP3 inflammasome in the context of AS treatment. A comprehensive literature search was conducted on databases such as PubMed/MEDLINE up to January 2025, yielding 38 eligible studies. Our analysis indicates that certain therapies can effectively prevent arterial inflammation in animal models by targeting multiple pathways and mechanisms related to the NLRP3 inflammasome. This review summarizes the primary findings of these studies, focusing on the therapeutic effects and underlying mechanisms of action. Based on these insights, we propose future strategies to enhance the efficacy, specificity, and safety of existing natural products and formulae for AS treatment. Additionally, this study offers a perspective for future research that may enhance our understanding of the roles and the mechanisms of CHM-derived phytochemicals and formulae in regulating the NLRP3 inflammasome and treating AS.

Deubiquitinating enzymes (DUBs) are a class of crucial peptidyl hydrolases within the ubiquitin system, playing a significant role in reversing and strictly regulating ubiquitination, which is essential for various biological processes such as protein stability and cellular signal transduction. Ubiquitin-specific protease 39 (USP39) is an important member of the DUBs family. Recent studies have revealed that USP39 is involved in the regulation of multiple cellular activities including cell proliferation, migration, invasion, apoptosis, and DNA damage repair. USP39 also plays a significant role in the development and progression of various cancers. It is believed that USP39 is a unique enzyme that controls the ubiquitin process and is closely associated with the occurrence and progression of many cancers, including hepatocellular, lung, gastric, breast, and ovarian cancer. This review summarizes the structural and functional aspects of USP39 and its research advancements in tumors, investigates the key molecular mechanisms related to USP39, and provides references for tumor diagnosis and treatment.

While PI3K/AKT/mTOR signalling plays a critical role in cancer, targeting this pathway with single node inhibitors has limited efficacy due to several known factors such as pathway feedback reactivation, co-occurring pathway mutations, and systemic glucose dysregulation leading to hyperinsulinemia. While multi-node inhibition approaches have shown promising clinical efficacy, they require further mechanistic characterisation.

Using models of endometrial and breast cancer, we evaluated the efficacy of a multi-node PI3K/AKT/mTOR pathway inhibitor approach utilising the dual mTORC1/mTORC2 inhibitor sapanisertib, PI3Kα inhibitor serabelisib and an insulin-supressing diet. Pathway signalling inhibition versus a range of single-node inhibitors was measured via S6, AKT and 4E-BP1 phosphorylation.

The serabelisib-sapanisertib combination more effectively suppressed PI3K/AKT/mTOR pathway signalling, particularly 4E-BP1, than single-node inhibitors, including alpelisib, capivasertib, inavolisib, everolimus and mutant-specific PI3K inhibitors RLY-2608 and STX-478. Serabelisib plus sapanisertib combined effectively with a range of other therapeutics, such as chemotherapies, hormone targeted therapies and CDK4/6 inhibitors. In xenograft models, sapanisertib, serabelisib plus paclitaxel/insulin supressing diet achieved complete inhibition of tumour growth/tumour regression.

Multi-node PI3K/AKT/mTOR pathway inhibition with serabelisib, sapanisertib and ISD is highly effective in preclinical models of endometrial and breast cancer, supporting continued clinical development in these and other solid tumours.

Non-small cell lung cancer (NSCLC) with PIK3CA mutations demonstrates significant challenges in treatment due to enhanced bone metastasis and immune checkpoint resistance. This study investigates the efficacy of tumor-targeting peptide 1-modified cancer stem cell-derived extracellular vesicles (TMTP1-TSRP-EVs) in reshaping the tumor microenvironment and reversing immune checkpoint resistance in NSCLC. By integrating TMTP1-TSRP into EVs, we aim to specifically deliver therapeutic agents to NSCLC cells, focusing on inhibiting the PI3K/Akt/mTOR pathway, a crucial driver of oncogenic activity and immune evasion in PIK3CA-mutated cells. Our comprehensive in vitro and in vivo analyses show that TMTP1-TSRP-EVs significantly inhibit tumor growth, reduce PD-L1 expression, and enhance CD8+ T cell infiltration, effectively reversing the immune-suppressive microenvironment. Moreover, the in vivo models confirm that our approach not only suppresses bone metastases but also overcomes primary resistance to immune checkpoint inhibitors by modulating the expression of key immunological markers. These findings suggest that targeted delivery of TMTP1-TSRP-EVs could provide a novel therapeutic strategy for treating PIK3CA-mutant NSCLC, offering significant improvements over traditional therapies by directly targeting the molecular pathogenesis of tumor resistance and metastasis. Molecular Mechanisms Reshaping the TME to Halt PI3K-Mutant Bone Metastasis of NSCLC and Overcoming Primary ICI Resistance. (Created by BioRender).

Immune checkpoint inhibitors have become a mainstay of treatment in many solid organ malignancies. Alongside this has been the rapid development in the identification and targeting of oncogenic drivers. The presence of alterations in oncogenic drivers not only predicts response to target therapy but can modulate the immune microenvironment and influence response to immunotherapy. Combining immune checkpoint inhibitors with targeted agents is an attractive therapeutic option but overlapping toxicity profiles may limit the clinical use of some combinations. In addition, there is growing evidence of shared resistance mechanisms that alter the response to immunotherapy when it is used after targeted therapy. Understanding this complex interaction between oncogenic drivers, targeted therapy and response to immune checkpoint inhibitors is vital for selecting the right treatment, at the right time for the right patient. In this review, we summarise the preclinical and clinical evidence of the influence of four common oncogenic alterations on immune checkpoint inhibitor response, combination therapies, and the presence of shared resistance mechanisms. We highlight the common resistance mechanisms and the need for more randomised trials investigating both combination and sequential therapy.

Background: Type 2 Diabetes Mellitus (T2DM) is associated with insulin resistance, hyperglycemia, and hyperlipidemia. Anthocyanins, which are natural antioxidants, have been reported to manage T2DM-related complications. However, the potential of anthocyanin-rich black wheat as a functional food for managing diabetes remains unexplored. Aim: This study aimed to investigate the effects of anthocyanin-rich black wheat on glucose metabolism, insulin sensitivity, lipid profile, oxidative stress, inflammation, and organ protection in high fat diet-streptozotocin (HFD-STZ) induced T2DM rats. Methods: T2DM was induced in rats using HFD-STZ. The rats were fed with either white wheat or anthocyanin-rich black wheat chapatti. Glucose metabolism, insulin sensitivity, lipid profile, antioxidant enzymes, inflammatory markers, and glucose transporters were assessed. Histopathological analysis of the liver, kidneys, and spleen was performed. Results: Compared to white wheat chapatti, black wheat chapatti exhibited higher α-amylase and α-glucosidase inhibitory activities. Black wheat chapatti consumption significantly reduced blood glucose and HbA1c levels, and improved insulin sensitivity, oral glucose tolerance, and insulin tolerance. Antioxidant enzyme (superoxide dismutase and catalase) activities were enhanced. Atherogenic dyslipidemia was attenuated, with improved high-density lipoprotein cholesterol levels. Inflammatory markers (TNF-α, IL-1β, leptin, resistin and cortisol) were reduced, while adiponectin (Acrp-30) levels increased. Black wheat chapatti activated adiponectin-AMPK and PI3K-AKT pathways, upregulating glucose transporters (GLUT-2 and GLUT-4). Histopathology revealed protective effects on the liver, kidneys, and spleen. Conclusions: Anthocyanin-rich black wheat chapatti ameliorates insulin resistance and associated complications in HFD-STZ-induced T2DM rats. It modulates key signaling pathways and glucose transporters, demonstrating its potential as a functional food for managing T2DM and its complications.