The uterus is a dynamic organ in which the endometrium undergoes cyclic processes of proliferation, shedding, and regeneration under the influence of estrogen and progesterone. In particular, estrogen regulates the proliferation and differentiation of the endometrium and plays an important role in the development of gynecological diseases such as endometrial cancer. Farnesyl diphosphate synthase (FDPS) is a key enzyme involved in the mevalonate pathway, catalyzing the synthesis of farnesyl pyrophosphate (FPP), which plays an essential role in cholesterol biosynthesis and protein prenylation. In this study, we demonstrated using an in vivo mouse model that the expression of FDPS is regulated by estrogen. FDPS expression was specifically elevated during the proestrus stage of the estrous cycle and subsequently decreased. In ovariectomized (OVX) mice, FDPS expression was significantly increased 24 h after estrogen treatment, whereas this response was suppressed by treatment with the estrogen receptor alpha (ERα) antagonist, ICI 182,780. Although FDPS expression has been reported in various cancers, its role in endometrial cancer remains unclear. Histological and cellular analyses revealed that FDPS is highly expressed in human endometrial cancer tissues and in the endometrial cancer cell line Ishikawa, where it contributes to cell proliferation. These findings suggest that FDPS may play a role in the survival and growth of endometrial cancer cells. This study provides new insights into the potential function of FDPS in the uterus and suggests that targeting FDPS may represent a promising therapeutic strategy for endometrial cancer.

Cancer is a heterogeneous disease at the cellular level and analyzing the genetic and molecular profile is essential for targeted therapy. Cancer cells continue to mutate, often resulting in drug resistance. In addition, cancers such as triple-negative breast cancer (TNBC) lack the target proteins used in some of the most effective therapies. This necessitates the identification of novel target proteins and biomarkers for effective treatment strategies. Ubiquitin E3 ligases are often differentially expressed in cancer cells, and numerous anticancer agents have been developed to inhibit them. SMURF2 is an E3 ligase that is differentially expressed in multiple cancer types. Although inhibiting upregulated SMURF2 may be strategically straightforward, enhancing the downregulated gene is often difficult. In addition, because E3 ligases ubiquitinate a variety of substrate proteins, targeting SMURF2 requires detailed analysis to achieve anticancer effect. This review discusses the dual role of SMURF2 in carcinogenesis and addresses the complex context-dependent function of SMURF2 in the various cellular pathways. In addition, resistance to existing cancer therapy related to SMURF2 and sensitivity mechanisms is discussed. Lastly, theranostic strategies for anticancer agents and biomarker development are suggested.

Small molecules either derived from cell metabolic reactions or produced by gut bacterial flora have shown the potential of affecting gene expression, which suggests the possibility of interactions able to modulate cellular functions. In this context, the reported experiments were aimed at verifying a possible interplay between lactate and butyrate in modulating the efficacy of antineoplastic drugs. Butyrate is a product of gut bacterial flora, shown to be endowed with anticancer properties; conversely, increased lactate levels in cancer cells were found to be associated with higher proliferation and drug resistance. For the reported experiments, we adopted two cell lines from clinically relevant, but different cancer forms: pancreatic and triple-negative mammary adenocarcinomas. In spite of their different tissue origin, the two cell lines appeared to similarly respond to the effects of the two metabolites, which were found to modulate in opposite ways the expression of key genes involved in DNA repair by homologous recombination. As a consequence, changed efficacy of this repair pathway and modified response to PARP inhibitors were observed. Notably, our results also suggest that the counteracting effect between these two metabolites may be leveraged to address additional challenges limiting the success of anticancer therapies.

Resistance to 5-fluorouracil (5-FU), a cornerstone chemotherapy for gastric cancer (GC), is a major clinical obstacle, often driven by the upregulation of its target enzyme, thymidylate synthase (TS). In this study, we investigated the potential of the pan-histone deacetylase inhibitor (HDACi) panobinostat to synergize with 5-FU. In GC cell lines, panobinostat treatment alone suppressed cell viability, clonogenicity, and migration, and this was associated with the induction of G1-phase cell cycle arrest and mitochondria-mediated apoptosis. Crucially, Panobinostat acted synergistically with 5-FU, leading to enhanced cytotoxicity. Mechanistically, 5-FU treatment alone induced a compensatory upregulation of TS protein, a known resistance mechanism. Panobinostat not only suppressed basal TS expression but, more importantly, abrogated this 5-FU-induced upregulation. Furthermore, panobinostat downregulated a network of oncogenes and cell cycle regulators, including c-Myc and key cyclins. These findings indicate that panobinostat can enhance 5-FU cytotoxicity by targeting TS expression and reprogramming oncogenic transcriptional networks, supporting its potential as a complementary strategy for overcoming fluoropyrimidine resistance in GC therapy.

Osteosarcoma (OS), a highly aggressive bone malignancy, is hard to treat due to complex molecular mechanisms. This study aimed to identify key bioactive compounds from medicine-food homologous (MFH) substances for OS intervention. We analyzed GEO transcriptomic data to get 317 differentially expressed genes (DEGs), screened bioactive compounds from 106 MFH via dual databases, predicted compound-DEG protein interactions with GraphBAN, and filtered 11 core compounds through drug-likeness/toxicity evaluations. Regulatory networks identified 5 key target genes (SOST, ACACB, TACR1, GRIN2B, MPO), 10 key compounds (e.g., ellagic acid dihydrate) and 8 MFHs (e.g., Daidaihua). Molecular docking/MD confirmed stable complexes. GSEA/GSVA revealed pathway dysregulation (e.g., upregulated WNT signaling), and immune analysis showed altered infiltration of 5 cell subsets. 143B cell experiments and qRT-PCR validated findings. MFH-derived compounds, especially ellagic acid dihydrate, have multi-target anti-OS potential, laying a foundation for novel OS therapeutics.

The mechanisms underlying carfilzomib (CFZ)-induced cardiotoxicity remain incompletely elucidated. In this study, we used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to characterize the transcriptional impact of CFZ and to evaluate whether atorvastatin could prevent these deleterious transcriptional changes. hiPSC-CMs were treated with 1 µM CFZ, CFZ + atorvastatin, atorvastatin, or vehicle control, followed by RNA sequencing, differential expression analyses, and pathway analyses. Transcriptomic profiling revealed a marked upregulation of genes in multiple proteasome subunits, including ATPase components (PSMC1, PSMC4, PSMC5, PSMC6) and non-ATPase regulatory subunits (PSMD1, PSMD2, PSMD12), suggesting a strong compensatory activation of proteostasis and protein quality-control pathways in response to CFZ exposure. In addition, several of the most significantly altered genes were those implicated in cardiomyopathy and heart failure, such as BAG3 and FLNC, and many heat-shock proteins, indicating the activation of cardiac stress-response pathways relevant to CFZ-associated cardiotoxicity. Atorvastatin co-treatment partially reversed a subset of CFZ-induced transcriptional changes, particularly within cholesterol biosynthesis and lipid-regulatory pathways (e.g., ACAT2 and ACTA1) but did not restore the CFZ-mediated downregulation of sarcomeric genes. Together, these findings define a multifactorial signature of deleterious CFZ-induced transcriptional changes and suggest that atorvastatin may provide partial metabolic, but not structural, cardio protection.

Iron (Fe) is an essential micronutrient for plant development and productivity. Nevertheless, the role of gibberellins (GAs) in the control of iron homeostasis is less studied compared to other growth regulators. We found that GAs modulate iron homeostasis in maize by inducing deficiency-like responses independent of rhizosphere iron availability. Plant phenotyping demonstrated that exogenous GA3 application under iron-sufficient conditions phenocopied iron deprivation, while inhibiting GA biosynthesis with mepiquat chloride prevented the development of typical symptoms of Fe deficiency (-Fe). Gibberellins positively control strategy II Fe uptake genes, albeit indirectly, as opposed to the direct negative transcriptional regulation of phytosiderophore biosynthesis. Additionally, gibberellins disrupt iron partitioning by suppressing root-to-shoot Fe translocation, causing iron overaccumulation in roots of GA3 treated plants. A functional ferrous iron uptake pathway was identified and was found to operate in conjunction with the strategy II uptake pathway via the differentially regulated Zea mays Iron-Regulated Transporter (IRT) paralogs ZmIRT1 and ZmIRT2. Root responses are spatially organized: gene expression in the lateral root sector reflects the shoot iron status, while transcriptional responses in the root apex correlate with local Fe demands. This study demonstrates that maize leverages a hybrid ferric/ferrous iron uptake strategy and establishes novel roles of GAs as pivotal regulators of iron homeostasis.

Salt stress is one of the main abiotic stresses that restrict crop production. Melatonin (MT), a signal molecule widely present in plants, plays an important role in regulating abiotic stress response. In this study, celery seedlings were used as experimental materials, and the control, salt stress, and exogenous MT treatment groups under salt stress were set up. Through phenotypic, physiological index determination, transcriptome sequencing, and expression analysis, the alleviation effects of MT on salt stress were comprehensively investigated. The results showed that exogenous MT treatment significantly reduced seedling growth inhibition caused by salt stress. Physiological measurements showed that MT significantly reduced malondialdehyde content, increased the activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT), promoted the accumulation of free proline and soluble protein, and increased photosynthetic parameters such as chlorophyll, ΦPSII, Fv/Fm, and ETR. Transcriptome analysis showed that MT regulates the expression of several genes associated with carbon metabolism, including β-amylase gene (AgBAM), sucrose-degrading enzyme genes (AgSUS, AgINV), and glucose synthesis-related genes (AgAG, AgEGLC, AgBGLU). The results of qRT-PCR verification were highly consistent with the transcriptome sequencing data, revealing that MT synergistically regulates starch and sucrose metabolic pathways, and effectively alleviates the damage of celery seedlings under salt stress at the molecular level. In summary, exogenous MT significantly improved the salt tolerance of celery by enhancing antioxidant capacity, maintaining photosynthetic function, promoting the accumulation of osmotic adjustment substances, and synergistically regulating carbon metabolism-related pathways. The concentration of 200 μM was identified as optimal, based on its most pronounced alleviating effects across the physiological parameters measured. This study provides an important theoretical basis for utilizing MT to enhance plant salt resistance.

Hericium erinaceus (H. erinaceus), a medicinal mushroom, is a source of bioactive compounds with demonstrated neuroprotective potential. This activity is primarily attributed to two distinct classes of compounds: erinacines from the mycelium, which potently induce the synthesis of neurotrophins, protein growth factors essential for neuronal survival and health, and hericenones from the fruiting body, which subsequently appear to enhance or potentiate neurotrophin-activated signaling pathways. Preclinical evidence substantiates their ability to enhance neurotrophin levels, particularly Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), and activate their cognate Trk receptors. Activation of these pathways, including PI3K/AKT/mTOR and MAPK/ERK, converges on transcription factors such as CREB, promoting neuronal survival, neurite outgrowth, and synaptic plasticity. However, the precise molecular mechanisms linking these small molecules to the complex orchestration of neurotrophic gene expression remain incompletely defined. This review synthesizes current knowledge of the neurotrophic pharmacology of H. erinaceus bioactives and proposes a novel framework suggesting that non-coding RNAs (ncRNAs) play a key regulatory role. We hypothesize that hericenones and erinacines modulate key transcriptional hubs, such as CREB, Nrf2, and NF-κB, which in turn regulate the expression of specific ncRNAs (e.g., miR-132, miR-146a) known to control neurogenesis, synaptogenesis, oxidative stress, and neuroinflammation. This ncRNA-mediated mechanism may represent an un-explored axis that explains the pleiotropic neuroprotective effects of these compounds. We critically appraise the existing preclinical evidence, identify significant methodological limitations and translational gaps, and propose a structured research roadmap to test these ncRNA-centric hypotheses, aiming to accelerate the rational development of H. erinaceus-derived compounds for neurodegenerative diseases.

This study aimed to elucidate the oncogenic role of FOXA1(forkhead box A1) in ovarian cancer and to evaluate its potential as both a therapeutic target and a diagnostic biomarker. We further investigated whether FOXA1 inhibition could enhance responsiveness to immune checkpoint blockade and overcome chemoresistance. A total of seventy-six ovarian tissue samples were analyzed, including nine normal, thirty-four benign, and thirty-three malignant specimens. IHC (immunohistochemistry) staining was performed to assess FOXA1 expression and its correlation with tumor stage. Functional studies were conducted using FOXA1 siRNA in SK-OV3 and HEYA8 cell lines. Changes in cell proliferation, migration, invasion, and wound-healing ability were evaluated following FOXA1 silencing. Quantitative RT-PCR was used to measure the expression of FOXA1 and EMT (epithelial-mesenchymal transition)-related genes. The effects of FOXA1 inhibition on sensitivity to carboplatin and the immune checkpoint inhibitor atezolizumab were also examined. IHC analysis revealed significant differences in FOXA1 expression among normal, benign, and malignant tissues, with levels correlating with tumor stage. FOXA1 silencing significantly reduced proliferation and decreased migration and invasion by 60-80%, accompanied by marked downregulation of EMT-related genes. Moreover, FOXA1 inhibition enhanced atezolizumab responsiveness and reduced carboplatin resistance in ovarian cancer cells. In summary, FOXA1 acts as an oncogenic driver in ovarian cancer, promoting proliferation, invasion, and EMT activation. Its overexpression correlates with disease progression, supporting its potential as a biomarker and therapeutic target. Targeting FOXA1 could enhance immunotherapy efficacy and help overcome chemoresistance in ovarian cancer.

Eutrema salsugineum is a model species for studying stress resistance, particularly extreme salinity, and is often compared with Arabidopsis thaliana. Previous research has shown that basal salicylic acid (SA) levels are significantly lower in E. salsugineum than in A. thaliana. In this study, subtractive hybridization revealed that SA-related genes were extensively induced in Arabidopsis but not in Eutrema. Using exogenous SA and the biosynthesis inhibitor paclobutrazol (PBZ), we further demonstrated that the low endogenous SA level in Eutrema significantly upregulates dehydroascorbate reductase (DHAR) and glutathione reductase (GR) gene expression, doubling the pools of total ascorbic acid and total glutathione. While SA treatment decreased the ratios of reduced ascorbic acid (ASA) to dehydroascorbate (DHA) and reduced glutathione (GSH) to oxidized glutathione (GSSG), PBZ treatment increased them, correspondingly modulating DHAR and GR activities and gene expression. The resulting enhancement of these key non-enzymatic antioxidants is a critical mechanism underpinning the superior salt tolerance of Eutrema.

The unfolded protein response (UPR) is a highly conserved adaptive mechanism that restores endoplasmic reticulum (ER) homeostasis under stress. Beyond its canonical roles in proteostasis, the UPR has emerged as a central regulator of immune responses across diverse contexts, including infection, inflammation, cancer, and autoimmunity. IRE1α, PERK, and ATF6 are three principal UPR sensors that coordinate complex signaling networks to regulate antigen presentation, cytokine production, and immune cell differentiation. This review highlights the molecular mechanisms by which small molecules target the UPR to modulate immune responses. In addition, we highlight stress granules (SGs) and the prevalence of protein-protein interactions mediated by intrinsically low-complexity domains (LCDs) in the UPR as potential new avenues for immune modulation. Finally, we discuss future directions for leveraging UPR modulation in immunotherapy, infectious disease, and chronic inflammatory disorders.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with resistance to 5-fluorouracil (5-FU) representing a major therapeutic challenge. Thymoquinone (TQ), a bioactive constituent of Nigella sativa, exhibits anticancer activity; however, the mechanisms underlying TQ-induced cell death appear to be highly context dependent. This study aimed to characterize cell line-specific death pathways triggered by TQ in colorectal cancer models with distinct molecular backgrounds and differential responsiveness to 5-FU. Human CRC cell lines RKO (5-FU-sensitive) and SW1116 (poorly responsive), along with normal colon epithelial cells (CCD-841CoN), were treated with TQ, 5-FU, or their combination for 24 h. Cell viability, DNA fragmentation, caspase-3/7, -8, and -9 activity, cell death phenotypes, and expression of apoptosis- and necroptosis-related genes were evaluated using MTT assays, ELISA, luminescent assays, flow cytometry, and RT-qPCR. TQ significantly reduced viability in both CRC cell lines while exerting minimal cytotoxicity toward normal cells. In RKO cells, characterized by microsatellite instability (MSI), TQ induced DNA fragmentation, caspase activation, and transcriptional upregulation of pro-apoptotic genes, consistent with apoptosis-associated signaling. In contrast, SW1116 cells, which exhibit chromosomal instability (CIN) and reduced responsiveness to 5-FU, displayed decreased viability accompanied by suppressed caspase activity and predominant features of caspase-independent necrotic cell death. This differential response may be attributed to the CIN phenotype, which has been associated with impaired apoptotic signaling and enhanced tolerance to cytotoxic stress. Combined TQ and 5-FU treatment did not produce synergistic cytotoxicity, as confirmed by Bliss independence analysis, but revealed distinct, cell line-dependent death programs. These findings demonstrate that TQ modulates cell death execution in a molecular context-dependent manner rather than enhancing 5-FU efficacy through pharmacological synergy.

Background:Malva sylvestris (the common mallow) is an herbaceous species widely used in ethnobotanical practices to treat gastrointestinal, hepatic and urinary inflammation. Objectives: Despite these beneficial effects on human health, the antineoplastic potential of this plant has not yet been fully explored. Thus, in the present study, two human colon cancer cell lines (i.e., HCT-116 and Caco-2) were treated with an extract obtained from M. sylvestris flowers (MFE), whose composition in terms of phytochemicals and microRNAs has been recently published by our research group, to explore its potential bioactivity. Methods/Results: MTT and Trypan blue assays demonstrated that MFE reduced tumour cell growth without causing significant cytotoxicity or apoptosis. Following the diphenylboric acid 2-aminoethyl ester-induced fluorescence of some plant metabolites, microscopy analysis proved that MFE components crossed the cell membranes, accumulating into nuclei. Wound assay and transwell tests documented that MFE was also able to reduce cell motility and invasiveness. In both cell lines qPCR experiments demonstrated that MFE caused the over-expression of factors, like VIMENTIN and E-CADHERIN, which negatively influence epithelial-mesenchymal transition in colon cancers. However, the effects of MFE appeared to be time-, dose- and cell type-dependent. In fact, the treatment induced senescence in P53-null Caco-2 cells (i.e., ROS, β-galactosidase and P21WAF1/Cip1) and a premise of differentiation (i.e., P27Kip1) in P53-wild-type HCT-116 cells, also via the CDK2/c-MYC/AKT axis, justifying its antiproliferative property. In parallel, the transfection of tumour cells with pure synthetic miR160b-5p-a microRNA identified in M. sylvestris flowers and predicted to target the human CDK2 transcript-resulted in gene silencing, thereby suggesting its central role in mediating the cross-kingdom effects of MFE on the investigated cancer models. Conclusions: Overall, these findings open new perspectives on the common mallow as a source of potential antimetastatic compounds and on the possible use of its plant microRNAs in the development of gene therapies.

Cancer remains a leading global cause of death, with conventional treatments often limited by toxicity and recurrence. Recent advances in gene therapy and nanodrug delivery offer new avenues for precision oncology. Human telomerase reverse transcriptase (hTERT) and glutathione peroxidase 4 (GPX4) are overexpressed in many cancers and linked to apoptosis and ferroptosis, respectively. Here, we developed a manganese dioxide nanosheet (MnO2-NS) probe co-loaded with antisense oligonucleotides targeting hTERT and GPX4 mRNA to synergistically down-regulate both genes and induce dual cell death pathways. The probe, assembled via adsorption of fluorescently labeled antisense strands, showed controllable release in the presence of glutathione (GSH). Cellular uptake and antisense release were confirmed in multiple cancer cell lines. The MnO2-NS probe significantly suppressed cell proliferation, outperforming single-target or carrier-only controls. Molecular analyses confirmed reduced hTERT and GPX4 expression, along with GSH depletion, ROS accumulation, and elevated lipid peroxidation-collectively promoting enhanced cancer cell death. In summary, this MnO2-NS-based co-delivery system enables synergistic gene silencing and GSH depletion, enhancing antitumor efficacy and providing a promising strategy for multifunctional nanotherapy.

We investigated the protective effects of skipjack tuna (Katsuwonus pelamis) bone-derived biocalcium (Bio) against dexamethasone-induced atrophy in C2C12 myotubes. Bio rescued atrophic morphology, increasing myotube diameter dose-dependently. It mitigated inflammation by suppressing nitric oxide production and the expression and concentration of proinflammatory cytokines (IL-6, TNF-α, IL-1β) significantly and dose-dependently. Bio restored protein turnover balance by downregulating MuRF1 and atrogin-1 while upregulating MTOR. At 5-20 µg/mL, Bio downregulated total NF-κB p65, p38 mitogen-activated protein kinase (MAPK), and FoxO3a and upregulated Akt expression. Crucially, Bio dose-dependently downregulated primary-, precursor-, and mature-microRNA-29b. In Bio-treated, dexamethasone-treated C2C12 myotubes, microRNA-29b inhibitor co-transfection significantly increased myogenin and MyoD expression, whereas microRNA-29b mimic co-transfection suppressed these myogenic markers, confirming the inhibitory role of microRNA-29b. Molecular docking simulations confirmed strong binding affinities between microRNA-29b and myogenin/MyoD. These results demonstrate that Bio exerts anti-atrophy effects by disrupting the microRNA-29b-mediated block on myogenesis and modulating inflammatory responses, protein turnover, and key signaling pathways. Collectively, skipjack tuna-derived Bio shows promise as a functional food supplement for sarcopenia prevention and management.

Flatfish metamorphosis is an abrupt post-embryonic transformation driven by thyroid hormones (THs), in which a bilaterally symmetric pelagic larvae becomes an asymmetric benthic juvenile. While the craniofacial changes associated with eye migration during metamorphosis are well documented, the role of THs in central nervous system (CNS) remodelling remains poorly understood. Here we investigated the role of THs on CNS remodelling during metamorphosis of the flatfish, Solea senegalensis, by integrating high-throughput transcriptomic analysis with experimental manipulation of TH availability using an inhibitor of hormone synthesis, methimazole (MMI) or exogenous T4. Transcriptome profiling revealed 567 differentially expressed gene transcripts associated with TH-levels involved in CNS development, neuronal and glial differentiation, migration, myelination and metabolism. Key CNS-related factors such as klf9, sox9, mbp, and plp were strongly down-regulated in MMI-treated larvae. Cell proliferation assays further demonstrated increased interocular neural proliferation under hypothyroidism, consistent with impaired differentiation. Region-specific analyses of the head and body uncovered distinct patterns of TH signalling involving dio2, dio3, thra, thrb, and mct8, underscoring the spatial complexity of endocrine regulation. These results highlight that THs are crucial for both morphological remodelling and CNS plasticity during flatfish metamorphosis, underscoring their conserved role in vertebrate brain development.

Prenatal arsenic exposure has been linked to a myriad of negative health effects. There is relatively little insight into the mechanisms and signaling alterations across different fetal organs that drive long-term immune-related issues following prenatal arsenic exposure. Therefore, the effects of this exposure window on gene expression in the liver, placenta, heart, and lung of gestation day (GD) 18 C57BL/6 mouse fetuses were investigated. From two weeks prior to mating until tissue collection at GD18, mice were exposed to 0 or 100 ppb sodium (meta) arsenite in drinking water, ad libitum. Genes of interest were analyzed by RT-qPCR, complemented with untargeted Agilent 44 K microarray analysis. Data cleanup and analysis was performed in RStudio. Differentially expressed mRNAs were queried in the String Database and using Cytoscape to create interaction networks and identify significantly enriched biological pathways. A total of 251, 165, 158, and 41 genes were significantly altered in the liver, placenta, heart, and lung, respectively, when treated samples were compared to controls. Many altered pathways were immune-related, supporting prior research. Most notably, gene expression of Gbp3, a key player in the cellular response to interferon gamma, was found to be reduced in placentas of male fetuses exposed to arsenic compared to controls (p = 0.0237). IMPACT: This is the first study comparing alterations in gene expression across multiple organs following prenatal exposure to environmentally relevant levels of arsenic. These findings, elucidating the multi-organ impact of prenatal arsenic exposure on predominantly immune-related pathways, further our mechanistic understanding of the long-term health effects observed in early-life arsenic-exposed populations.

Sarcomas are a heterogeneous group of cancers with few shared therapeutic targets. We show that PI3K signaling is frequently activated in sarcomas due to PTEN loss (in 30%-60%), representing a common therapeutic target. The PI3K pathway has lacked a downstream oncogenic transcription factor. We show TAZ and YAP are transcriptional coactivators regulated by PI3K and drive a transcriptome necessary for tumor growth in a PI3K-driven sarcoma mouse model. This PI3K/TAZ/YAP axis exists in parallel to the known PI3K/AKT/mTORC1 axis, providing a rationale for combination therapy targeting the TAZ/YAP-TEAD interaction and mTORC1. Combination therapy using IK-930 (TEAD inhibitor) and everolimus (mTORC1 inhibitor) synergistically diminished proliferation and anchorage-independent growth of PI3K-activated sarcoma cell lines at low, physiologically achievable doses. Furthermore, this combination therapy showed a synergistic effect in vivo, suggesting that an integrated view of PI3K and Hippo signaling can be leveraged therapeutically in PI3K-activated sarcomas.

Irinotecan, a standard therapeutic agent for metastatic colorectal cancer (mCRC), often faces significant limitations due to drug resistance, with treatment failure observed in approximately 30%-50% of patients, leading to poor clinical outcomes. This study aims to systematically elucidate the molecular mechanisms underlying irinotecan resistance in colorectal cancer (CRC) by constructing patient-derived organoid (PDO) models combined with single-cell transcriptomics technology.