Dual BRD4/AKT inhibition overcomes c-MYC-driven resistance in metastatic castration-resistant prostate cancer.

The potential of Humulus scandens in delaying non-small cell lung cancer: Targeting the PI3K/Akt signaling pathway to inhibit tumor growth and metastasis.

Heart failure remains a leading cause of mortality worldwide with limited therapeutic options. Xinyang Tablet (XYT), a clinically used traditional Chinese medicine, demonstrates cardioprotective effects, but its mechanisms against cardiac hypertrophy remain unclear. This study aimed to elucidate the therapeutic mechanisms of XYT in heart failure with a focus on oxidative stress and hypertrophy pathways. Pressure-overload heart failure was induced by transverse aortic constriction (TAC) in mice. Cardiac function was assessed via histology (hematoxylin-eosin [H&E], Masson's trichrome), oxidative stress markers (dihydroethidium [DHE] staining, superoxide dismutase [SOD]/malondialdehyde [MDA]/glutathione peroxidase [GSH-Px] assays), and molecular analyses. In vitro, angiotensin II (AngII)-treated HL-1 cardiomyocytes evaluated hypertrophy and oxidative stress responses. Multiomic approaches, including ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS), network pharmacology, RNA sequencing (RNA-seq), and single-cell RNA sequencing (scRNA-seq), identified XYT's bioactive compounds and hub targets, validated by AKT inhibitor (MK-2206) experiments. XYT attenuated TAC-induced cardiac hypertrophy and fibrosis, reducing heart volume, cardiomyocyte cross-sectional area, and fibrotic markers (collagen type I alpha 1 [COL1A1]/collagen type III alpha 1 [COL3A1]). XYT suppressed oxidative stress by decreasing reactive oxygen species (ROS)/NADPH oxidase 2 (NOX2)/NOX4 while increasing superoxide dismutase 2 (SOD2)/GSH-Px in vivo and in vitro. Bioinformatics identified 18 hub genes (e.g., histone deacetylase 2 [HDAC2], SOD2) and enriched phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)/oxidative stress pathways. XYT inhibited HDAC2/AKT/glycogen synthase kinase-3β (GSK-3β) phosphorylation, while AKT inhibition with MK-2206 mimicked XYT's protective effects. XYT ameliorates heart failure by targeting HDAC2 to suppress AKT/GSK-3β signaling, mitigating oxidative stress, cardiac hypertrophy, and fibrosis, providing mechanistic evidence for clinical translation.

MIP-8, a Morchella importuna-derived peptide, protects against 6-OHDA-induced neurotoxicity via AKT signaling modulation.

EphA2 is a receptor tyrosine kinase that suppresses tumor growth when bound by its ligand ephrin-A1 (EA1), but promotes tumor progression in the absence of ligand. In hepatocellular carcinoma (HCC) cells, EphA2 is proteolytically cleaved by membrane-type 1 matrix metalloproteinase (MT1-MMP), producing a C-terminal fragment (EphA2-CF) and an N-terminal fragment (EphA2-NF). The functional role of these cleavage fragments on HCC remains unclear. Herein, we investigated their roles in hepatocarcinogenesis and malignant progression. Western blotting and membrane biotinylation assays revealed that EphA2-CF was present in HCC cells co-expressing EphA2 and MT1-MMP. EphA2-CF-expressing cells were resistant to EA1-induced growth suppression, while MT1-MMP knockdown restored EA1 sensitivity. In Hep3B cells, stable EphA2-CF expression confirmed resistance to EA1-mediated inhibition of proliferation and survival. Mechanistically, EphA2-CF sustained oncogenic signaling through constitutive phosphorylation at EphA2-S897, while failing to induce Y588 phosphorylation after EA1 stimulation. Mutation of EphA2-S897 abolished EphA2-CF-driven proliferation and survival. Reverse-phase protein array identified activation of the EGFR-AKT axis and inactivation of GSK3β as key downstream events. Both pharmacological inhibition of EGFR or AKT, and activation of GSK3β suppressed EphA2-CF-driven proliferation. Furthermore, enforced expression of a constitutively active GSK3β mutant (S9A) markedly suppressed EphA2-CF-driven tumorigenesis in mice, genetically validating GSK3β inactivation as a critical effector of EphA2-CF oncogenic signaling. In addition, soluble EphA2-NF functioned as a decoy receptor for EA1, blocking its tumor-suppressive activity. These findings demonstrate that MT1-MMP-mediated EphA2 processing promotes HCC malignancy via dual mechanisms: EphA2-CF drives ligand-independent EGFR/AKT/GSK3β signaling, while EphA2-NF inhibits EA1-mediated tumor suppression.

Genome-wide copy number analysis identifies AKT as a novel therapeutic target in pleural mesothelioma.

ABSTRACT Background Capivasertib was the first AKT inhibitor approved by the US FDA as a second-line treatment for PIK3CA/AKT1/PTEN-altered, HR+/HER2- advanced breast cancer. However, capivasertib is costly. This study provides the first evidence on the financial impact for third-party payers to reimburse capivasertib. Research design and methods We estimated the change in total costs from adding capivasertib to the treatment mix over 3 years. The size of the target population was estimated using data on incidence and prevalence for breast cancer, PIK3CA/AKT1/PTEN alterations, and risk of failure to first-line treatment. Costs associated with drug administration, disease management, and adverse events were captured. Costs were measured in 2023 US dollars. Results In a 1-million-member population, 113, 114, and 115 individuals would be eligible for capivasertib treatment in years 1, 2, and 3, respectively. Adding capivasertib to the second-line setting would add $31,939,838 in net costs over 3 years. Specifically, drug costs would increase by $34,251,781 but would be offset by savings of $323,632 in adverse event costs and of $1,988,311 in follow-up costs. These net costs amount to $0.88 per-member-per-month. Conclusion While introduction of capivasertib could reduce adverse event and follow-up costs, it may result in an overall increase in payers’ budget.

In Vitro and In Silico Evaluation of the Anticancer Potential of Ethanolic Seed Extract of Bryonia laciniosa against Colorectal and Hepatocellular Cancer".

Imeglimin enhances GLUT4-mediated glucose uptake and is more effective than metformin in 3T3-L1 adipocytes.

AKT1 glutarylation regulated by GCDH and SIRT5 suppresses oncogenic signaling.

Network pharmacology and transcriptomic analysis reveal wogonin as a key bioactive compound of Scutellaria baicalensis Georgi in suppressing glioma progression via PI3K-Akt pathway suppression.

AKT1 is a member of the AGC kinase family and represents a key therapeutic target in cancer. Although ATP-competitive compounds can act as potent inhibitors of AKT1, they may also exhibit off-target interactions with other kinases in the PI3K/AKT/mTOR pathway, a critical issue that requires systematic investigation. To address this challenge, we propose a computational framework that integrates a deep learning (DL) model with physics-based modeling approaches. Specifically, the developed DL model, CrossAtt-DTI, was first employed to perform binary classification and identify potential AKT1 binders. Subsequently, multiple molecular docking tools were used to predict binding conformations and identify poses that capture key binding residues. The stability of these docked conformations was then evaluated through all-atom molecular dynamics simulations in explicit solvent, followed by MM/PBSA calculations. The proposed framework was initially validated and subsequently applied to investigate the off-target interactions of ATP-competitive inhibitors with other kinases. The results indicate that, in addition to off-target interactions with members of the AGC kinase family predicted for most ATP-competitive inhibitors, Ipatasertib and NTQ1062 may exhibit strong interactions with PI3Kα, a member of the PI3K kinase family, while NTQ1062 may also interact with mTOR, a member of the PI3K-related kinase family. However, further in vitro and in vivo studies are required to validate these potential interactions. Overall, this work establishes a hybrid deep learning and physics-based computational framework for predicting the off-target effects of ATP-competitive AKT1 inhibitors and provides mechanistic insights into kinase cross-reactivity within the PI3K/AKT/mTOR signaling pathway.

Nasopharyngeal carcinoma (NPC) remains a therapeutic challenge, particularly in the recurrent or treatment-refractory setting, underscoring the need for tumor-selective therapeutic strategies. In this study, we applied a tumor-normal-paired high-throughput drug sensitivity screening approach using two biologically distinct NPC cell lines, EBV-positive C666-1 and EBV-negative CNE2, together with normal nasopharyngeal epithelial cells as a normal control. This design enabled direct identification of compounds with selective anti-NPC activity while sparing normal counterpart. Drug sensitivity profiling identified several agents with established clinical relevance in NPC, validating the screening strategy. Among novel candidates, the AKT inhibitor capivasertib emerged as a highly selective inhibitor of NPC cell viability, with IC₅₀ values in the nanomolar to low micromolar range. Capivasertib demonstrated synergistic activity with platinum-based chemotherapy and enhanced radiosensitivity in NPC cells. In vivo, capivasertib significantly suppressed tumor growth and its combination with cisplatin significantly prolonged survival in xenograft models without inducing overt systemic toxicity. Mechanistically, capivasertib treatment increased AKT phosphorylation, consistent with pharmacodynamic target engagement, while suppressing downstream mTOR/4EBP1 signaling and inducing pro-apoptotic levels. Collectively, these findings demonstrate that Akt/mTOR inhibition by capivasertib enhances therapeutic efficacy in preclinical NPC models and provides rationale for further clinical evaluation of capivasertib in advanced NPC.

While targeted therapies have improved outcomes in lung adenocarcinoma (LUAD), many patients still lack targetable mutations. Here, we identified alpha-L-fucosidase 2 (FUCA2) as a crucial driver of LUAD by preventing cellular senescence. Mechanistically, through the restriction of fucosyltransferase 3 (FUT3)-mediated α-1,3-fucosylation of ErbB3 at Asn437, FUCA2 safeguarded ErbB3-ErbB2 heterodimerization to promote ErbB3 activation and sustain persistent AKT signaling. Active AKT prevented p53 protein stabilization in TP53-wild-type LUAD cells and inhibited p27 protein accumulation in TP53-mutant LUAD cells, thereby counteracting senescence and supporting malignant growth. Notably, low-dose Capivasertib, an AKT inhibitor targeting tumors with PIK3CA/AKT1/PTEN mutation(s), induced senescence selectively in FUCA2-high LUAD irrespective of PIK3CA/AKT1/PTEN/TP53 mutational status, and its combination with the nutraceutical senolytic procyanidin C1 achieved potent and low-toxicity suppression of LUAD across multiple preclinical models. Together, our results uncover the FUCA2-ErbB3 fucosylation-AKT pathway as a central regulator of senescence and propose a FUCA2-guided drug repurposing strategy for LUAD.

Aberrant phosphatidylinositol 3-kinase (PI3K) activation drives many cancers, but PI3K inhibitors like Pictilisib often induce cytostasis rather than cytotoxicity, limiting their therapeutic potential. Here we demonstrate that PI3K inhibition combined with nutrient stress triggers methuosis, a non-apoptotic form of programmed cell death characterized by dysregulated macropinosomes. This response occurs selectively in PI3K-aberrant cancer cells that maintain macropinocytic uptake despite PI3K inhibition. Methuosis-associated vacuoles originate from macropinosomes that retain endosomal markers but fail to undergo lysosomal fusion. Active macropinocytic uptake is essential for methuosis, as demonstrated by suppression with EIPA and Bafilomycin A1, whereas the AKT inhibitor MK2206 has no effect, establishing that direct PI3K inhibition, rather than AKT signaling, is required. Mechanistically, PI3K blockade prevents conversion of phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2) to phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) causing PI(4,5)P2 to accumulate on internalizing macropinosomal membranes. This aberrant PI(4,5)P2 enrichment impairs ion channel function across multiple channel families, disrupting intracellular osmotic balance. Ion dysregulation triggers aquaporin-1-mediated water influx, driving catastrophic vacuolar expansion and cell death. Although Pictilisib activates pro-survival autophagy, this fails to prevent methuosis-mediated cytotoxicity. In xenograft models, dietary restriction synergizes with Pictilisib to suppress tumor growth, correlating with pronounced intratumoral vacuolization. These findings reveal that combining PI3K inhibition with nutrient restriction converts cytostatic responses into methuosis-driven cytotoxicity via PI(4,5)P2-dependent macropinocytic dysregulation, providing a rational pharmacologic-dietary strategy to enhance PI3K-targeted cancer efficacy.

Vascular endothelial dysfunction because of environmental mercuric chloride (HgCl2) exposure is well known to induce cardiovascular diseases and heightened vascular responsiveness to angiotensin II (Ang 1-8). The PI3K/AKT/eNOS signaling pathway is essential for preserving endothelial NO bioavailability. Nevertheless, the reasons underlying this dysfunction during oxidative stress are inadequately elucidated.This study explored the roles of L-arginine (LA) and tetrahydrobiopterin (BH4) both alone and in combination on Ang1-8-induced vascular responses via the endothelial PI3K/AKT/eNOS pathway against HgCl2 -induced vascular dysfunction in rat aortic rings.In comparison to control (CT) rings; HgCl2 markedly modified Ang1-8 vascular reactivity, consistent with eNOS uncoupling and oxidative dysregulation. Inhibition of PI3K or AKT further amplified these effects, thereby confirming the vasoprotective role of the PI3K/AKT/eNOS system. The co-administration of LA and BH4 significantly restored both Emax and pD2 values in the presence of HgCl2 and inhibitors, indicating improved NO bioavailability and re-coupled eNOS activity.Treatments of LA and BH4 together sustained endothelial PI3K/AKT/eNOS signaling and alleviate HgCl2-induced vascular hyperreactivity to Ang1-8 through restoration of NO/cGMP-mediated relaxation, reduces oxidative damage, and enhances antioxidant capacity. These results highlight a potential therapy strategy focused on resolving substrate-cofactor coupling and reinstating endothelial signaling to mitigate heavy metal-induced vascular dysfunction.

ABSTRACTMelatonin signalling, mediated by membrane receptors and tightly regulated biosynthetic enzymes, is a key component of circadian and neuroendocrine control in the brain. However, whether the tryptophan–melatonin axis remains hierarchically intact during glioma progression and how its disruption affects downstream signalling remain unclear. In this study, transcriptomic data from TCGA, CGGA, and GTEx were integrated to characterize the expression patterns of melatonin receptors (MTNR1A and MTNR1B) and biosynthetic enzymes (AANAT and ASMT) across normal brain tissue, lower‐grade glioma and glioblastoma. Protein expression was validated by immunohistochemistry, and functional consequences were investigated through gain‐ and loss‐of‐function experiments in glioma cells, followed by proliferation, migration, invasion, apoptosis and signalling analyses. Multi‐layered analyses revealed a coordinated disruption of the tryptophan–melatonin axis during glioma progression. Expression of AANAT, ASMT, MTNR1A and MTNR1B progressively declined with increasing tumour grade and was associated with poor prognosis. Immunohistochemistry confirmed reduced MTNR1A and ASMT protein expression in glioma tissues. Restoration of these factors suppressed glioma cell proliferation, migration and invasion while promoting apoptosis. Mechanistically, these effects were accompanied by inhibition of AKT, ERK and STAT3 signalling. These findings demonstrate that hierarchical disruption of receptor‐ and synthesis‐dependent melatonin signalling is a defining molecular feature of glioma and may contribute to malignant progression through activation of AKT/ERK/STAT3 pathways, providing new insights into the biological and therapeutic relevance of the tryptophan–melatonin axis in glioma.

The objective of this study was to investigate the effects of alginate oligosaccharides on wound cell proliferation, migration, apoptosis, macrophage polarisation, and wound healing. The results of the Cell Counting Kit-8, Transwell method, and caspase-3 immunofluorescence showed that alginate oligosaccharides effectively promoted keratinocyte proliferation, migration, and reduced apoptosis by activating the PI3K/AKT1 signalling pathway. The polarisation of macrophages was detected using iNOS and Arg-1 immunofluorescence. Alginate oligosaccharides induced M2 polarisation. This was negated after using an AKT1 inhibitor. In vitro cell experiments showed that alginate oligosaccharides did not affect macrophage proliferation but showed a significant reduction in macrophage numbers in in vivo animal wound models, accompanied by a trend in M2 polarisation. Although AOs had no direct in vitro antibacterial effect, their in vivo application modulated the composition of wound microbiota, which may be related to AOs induced macrophage M2 polarization and the improvement of local inflammatory response. The combined effects of alginate oligosaccharides on keratinocytes and macrophages ultimately promoted wound healing and altered microbiota composition, thereby providing a new, potential treatment option for wound healing(Fig. 1).

Mild photothermal therapy (MPTT) offers a safe thermal window but typically fails to trigger sufficient immunogenic inflammation for durable tumor control. Reprogramming the "cold" tumor microenvironment into a pro-inflammatory state is essential for effective immunotherapy. We established a synchronized intervention strategy combining MPTT with CDK12/13 inhibition (SR4835) and TGF-β blockade (SB431542). We investigated the molecular crosstalk between ferroptosis and apoptosis and its impact on remodeling the tumor inflammatory landscape. Mechanistically, MPTT intensified ROS-driven lipid peroxidation to potentiate ferroptosis, while SR4835 perturbed the CDK12/13-AKT axis to activate mitochondrial apoptosis. This synergy generated a robust pro-inflammatory immunogenic cell death (ICD) phenotype. Furthermore, TGF-β blockade dismantled immunosuppression, restoring the CD8⁺/Treg balance and fostering a pro-inflammatory cytokine milieu. Consequently, this regimen suppressed primary and distant tumors, reduced metastasis, and notably prevented tumor recurrence by activating memory T cells, thereby establishing durable vaccine-like immunity. These findings demonstrate that orchestrating ferroptosis-apoptosis crosstalk effectively reprograms the immune microenvironment. By repositioning MPTT from a local thermal tool to a driver of antitumor inflammation, this study establishes a mechanism-based framework for treating immunologically cold solid tumors.

The Therapeutic Effect of Polydeoxyribonucleotide on Lung Ischemia-Reperfusion Injury.