Search Results (1,744)

Background/Objectives: Retinal ischemia–reperfusion (I/R) injury is a common mechanism in glaucoma, diabetic retinopathy, and retinal vein occlusion, leading to progressive loss of retinal ganglion cells (RGCs). This study investigates the regulatory role of miR-21-5p and its interaction with Signal Transducer and Activator of Transcription 3 (STAT3) in retinal I/R injury. Methods: An acute intraocular hypertension (AIH) rat model was used to induce retinal I/R. The interaction between miR-21-5p and STAT3 was examined by dual-luciferase reporter assays. miR-21-5p and STAT3 expression were quantified by qRT-PCR and Western blotting. Retinal morphology, microglial polarization, and RGC survival were assessed by H&E staining and immunofluorescence. In vitro, microglia and RGCs were subjected to oxygen–glucose deprivation/reperfusion (OGD/R), and microglial-conditioned media (MCM) were applied to RGCs. Results: (1) miR-21-5p ameliorated AIH-induced retinal damage in vivo. (2) Overexpression of miR-21-5p inhibits M1 polarization of RM cultured in vitro. (3) MCM from miR-21-5p-overexpressing microglia attenuated OGD/R-induced RGC death. (4) miR-21-5p downregulates STAT3 expression to inhibit RM M1 polarization. (5) miR-21-5p down-regulation of STAT3 levels inhibits M1 polarization and reduces apoptosis of RGCs in retinal microglia of AIH rats. Conclusions: miR-21-5p alleviates retinal I/R injury by restraining microglial M1 polarization through direct repression of STAT3, thereby promoting RGC survival. These findings identify the miR-21-5p/STAT3 axis as a potential therapeutic target for ischemic retinal diseases. Full article

Background: Type 2 diabetes mellitus (DM) is a major cardiovascular risk factor that induces monocyte dysfunction and contributes to their accumulation in atherosclerotic lesions. Monocyte recruitment and accumulation in the tissues contribute to chronic inflammation and are essential to the pathobiology of diabetes-induced atherosclerosis. However, the mechanisms that drive the accumulation of monocytes in the diabetic environment are not clearly understood. Methods: Primary monocytes from type 2 (T2) DM and non-T2DM individuals were isolated using magnet-assisted cell sorting. To examine the influence of a diabetic milieu on monocyte function, monocytes from T2DM patients, db/db mice, or human monocytes subjected to hyperglycaemia were analysed for their responses to pro-atherogenic cytokines using Boyden chamber assays. Furthermore, the interactions of non-diabetic and diabetic monocytes with TNFα-inflamed endothelium were studied using live-cell imaging under physiological flow conditions. RT-qPCR and FACS were used to study the expression of relevant molecules involved in monocyte-endothelium interaction. Results: CD14⁺CD16⁻ monocytes isolated from T2DM patients or monocytes exposed to hyperglycaemic conditions showed reduced chemotactic responses towards atherosclerosis-promoting cytokines, CCL2 and CX3CL1, indicating monocyte dysfunction. Under flow conditions, the transendothelial migration (TEM) capacity of T2DM monocytes was significantly reduced. Even though these monocytes adhered to the endothelial monolayer, only a few transmigrated. Interestingly, the T2DM monocytes and monocytes exposed to hyperglycaemic conditions accumulated in the ablumen following transendothelial migration. The time period in the ablumen of T2DM cells was prolonged, as there was a significant impairment of the reverse transendothelial migration (rTEM). Mechanistically, the T2DM milieu specifically induced the activation of monocyte integrins, Macrophage-1 antigen (Mac-1; integrin αMβ2 consisting of CD11b and CD18), and Lymphocyte function-associated antigen 1 (LFA-1; αLβ2 consisting of CD11a and CD18). Furthermore, elevated levels of CD18 transcripts were detected in T2DM monocytes. Junctional Adhesion Molecule 3 (JAM-3)–MAC-1 interactions are known to impede rTEM and T2DM milieu-potentiated JAM-3 expression in human coronary artery endothelial cells (HCAEC). Finally, the overexpression of JAM-3 on HCAEC was sufficient to completely recapitulate the impaired rTEM phenotype. Conclusions: Our results revealed for the first time that the enhanced T2DM monocyte accumulation in the ablumen is not secondary to the elevated transmigration through the endothelium. Instead, the accumulation of monocytes is due to the direct consequence of a dysfunctional rTEM, potentially due to enhanced JAM3-MAC1 engagement. Our results highlight the importance of restoring the rTEM capacity of monocytes to reduce monocyte accumulation-dependent inflammation induction and atherogenesis in the T2DM environment. Full article

Sindbis virus (SINV) is a mosquito-borne alphavirus capable of causing neurological and immunological symptoms in humans, yet its effects on neural/immune systems remain insufficiently characterized. This study aimed to examine SINV replication, UV-C light inactivation, apoptosis induction, and immune gene modulation in human SH-SY5Y neuroblastoma cells. Following viral adaptation and infectious dose determination, SINV replication and inactivation were assessed using RT-qPCR and dsRNA immunofluorescence. Apoptotic markers (caspase-3, Bax, Bcl-2) were analyzed by immunofluorescence and immune genes expression kinetics (TLR3/7, RIGI, MDA5, IL-1β, IL-6, TNFα, IL-10, IFNβ and β-catenin) were measured at defined time points post-infection by RT-qPCR. SH-SY5Y cells supported productive SINV infection, with viral RNA detectable as early as 3 hpi and marked cytopathic effects by 24 hpi. A custom-built UV-C chamber achieved complete viral inactivation following 3 × 30 s exposures. We observed SINV time-course replication and UV-C inactivation with conspicuous morphological alterations in SH-SY5Y cells. Furthermore, SINV triggered caspase-dependent apoptosis and robust transcriptional upregulation of innate immune genes, peaking between 12–16 hpi and declining by 30 hpi. These findings elucidate the temporal dynamics of SINV replication, cell death mechanisms, and immune activation in a neuronal context, contributing to a better understanding of SINV neuropathogenesis. Full article

Acute myeloid leukemia is characterized by the presence of malignant cells and their uncontrolled growth in bone marrow. Recent studies have been focused on the ability of curcumin, a polyphenol derived from the Curcuma longa plant. The role of curcumin is currently under investigation, due to its antitumor properties and action on several pathways, including Nuclear Factor kappa-light-chain-enhancer of activated B cells, Signal Transducer and Activator of Transcription 3, Phosphatidylinositol 3-kinase/protein kinase B, and mitogen-activated protein kinase. The aim of this review is to demonstrate the possible anti-leukemic effect of curcumin, thus its ability to induce apoptosis, inhibit cell proliferation, and modulate angiogenesis. Nowadays, although multiple synergistic effects have been observed and curcumin’s efficacy has been demonstrated through several in vivo and in vitro studies, further broad and exhaustive scientific research is needed to confirm the considerable results. In fact, the low bioavailability of curcumin has limited its clinical applications, a challenge that is currently being addressed through the development of nanoformulations to enhance its stability and absorption within the body. In conclusion, curcumin exhibits antitumor properties with a favorable profile, suggesting its potential as a supportive adjunct in the treatment of patients with acute myeloid leukemia. Full article

Extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitors show therapeutic potential in triple-negative breast cancer (TNBC), but resistance through compensatory signaling limits their efficacy. We previously identified the secretory carrier membrane protein 3 (SCAMP3) as a regulator of TNBC progression and ERK1/2 activation. Here, we investigated the role of SCAMP3 in ERK1/2 signaling and therapeutic response using TMT-based LC-MS/MS phosphoproteomics of wild-type (WT) and SCAMP3 knockout (SC3KO) SUM-149 cells under basal conditions, after epidermal growth factor (EGF) stimulation, and during ERK1/2 inhibition with MK-8353. A total of 4408 phosphosites were quantified, with 1093 significantly changed. SC3KO abolished residual ERK activity under MK-8353 and affected the compensatory activation of oncogenic pathways observed in WT cells. SC3KO reduced the phosphorylation of ERK feedback regulators RAF proto-oncogene serine/threonine-protein kinase Raf-1 (S43) and the dual-specificity mitogen-activated protein kinase kinase 2 (MEK2) (T394), affected other ERK targets, including nucleoporins, transcription factors, and metabolic enzymes triosephosphate isomerase (TPI1) (S21) and ATP-citrate lyase (ACLY) (S455). SCAMP3 loss also impaired the mammalian target of rapamycin complex I (mTORC1) signaling and disrupted autophagic flux, evidenced by elevated sequestosome-1 (SQSTM1/p62) and microtubule-associated protein light chain 3 (LC3B-II) with reduced levels of the autophagosome lysosome maturation marker, Rab7A. Beyond ERK substrates, SC3KO affected phosphorylation events mediated by other kinases. These findings position SCAMP3 as a central coordinator of ERK signaling and autophagy. Our results support SCAMP3 as a potential therapeutic target to enhance ERK1/2 inhibitor clinical efficacy and overcome adaptive resistance mechanisms in TNBC. Full article

Background/Objectives: Cancer progression is characterized by the suppression of apoptosis, activation of metastatic processes, and dysregulation of cell proliferation. The proper functioning of these mechanisms relies on critical signaling pathways, including Phosphoinositide 3-kinase/Protein kinase B/mammalian Target of Rapamycin (PI3K/Akt/mTOR), Mitogen-Activated Protein Kinase (MAPK), and Signal Transducer and Activator of Transcription 3 (STAT3). Although curcumin and resveratrol exhibit anticancer properties and affect these pathways, their pharmacokinetic limitations, including poor bioavailability and low solubility, restrict their clinical application. The aim of our study was to evaluate the synergistic anticancer potential of curcumin and resveratrol through hybrid molecules rationally designed from these compounds to mitigate their pharmacokinetic limitations. Furthermore, we analyzed the multi-target anticancer effects of these hybrids on the AKT serine/threonine kinase 1 (AKT1), MAPK, and STAT3 pathways using in silico molecular modeling approaches. Methods: Three hybrid molecules, including a long-chain (ELRC-LC) and a short-chain (ELRC-SC) hybrid, an ester-linked hybrid, and an ether-linked hybrid (EtLRC), were designed using the Avogadro software (v1.2.0), and their geometry optimization was carried out using Density Functional Theory (DFT). The electronic properties of the structures were characterized through Frontier Molecular Orbital (FMO), Molecular Electrostatic Potential (MEP), and Fourier Transform Infrared (FTIR) analyses. The binding energies of the hybrid molecules, curcumin, resveratrol, their analogs, and the reference inhibitor were calculated against the AKT1, MAPK, and STAT3 receptors using molecular docking. The stabilities of the best-fitting complexes were evaluated through 100 ns molecular dynamics (MD) simulations, and their binding free energies were estimated using the Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) method. Results: DFT analyses demonstrated stable electronic characteristics for the hybrids. Molecular docking analyses revealed that the hybrids exhibited stronger binding compared to curcumin and resveratrol. The binding energy of −11.4 kcal/mol obtained for the ELRC-LC hybrid against AKT1 was particularly remarkable. Analysis of 100 ns MD simulations confirmed the conformational stability of the hybrids. Conclusions: Hybrid molecules have been shown to exert multi-target mechanisms of action on the AKT1, MAPK, and STAT3 pathways, and to represent potential anticancer candidates capable of overcoming pharmacokinetic limitations. Our in silico-based study provides data that will guide future in vitro and in vivo studies. These rationally designed hybrid molecules, owing to their receptor affinity, may serve as de novo hybrid inhibitors. Full article

Background: Treatment with androgen receptor (AR) signaling inhibitors, such as enzalutamide, can induce neural lineage plasticity in prostate cancer, potentially progressing to t-NEPC. However, the molecular mechanisms underlying this enzalutamide-driven plasticity, particularly the contribution of immune signaling pathways, remain poorly understood. Methods: We analyzed transcriptomic profiles of patient samples and prostate cancer cell lines to investigate changes in immune signaling pathways. Interferon gamma (IFNγ), interferon alpha (IFNα), and interleukin 6 (IL6)-Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling were assessed in enzalutamide-sensitive and -resistant prostate cancer cells. Functional assays were conducted to examine cell responsiveness to cytokine stimulation and susceptibility to STAT1 inhibition using fludarabine. Results: Immune-related pathways, including IFNγ, IFNα, IL6-JAK-STAT3, and inflammatory responses, were significantly suppressed in NEPC patient samples compared to those with castration-resistant prostate cancer (CRPC). Enzalutamide-resistant and NEPC cells exhibited markedly impaired IFNγ and IL6 signaling. In contrast, early-stage enzalutamide treatment paradoxically enhanced IFNγ and IL6 responsiveness. Transcriptomic profiling revealed coordinated upregulation of E2F target genes and activation of IFNα/IFNγ and JAK/STAT signaling pathways during early treatment. Importantly, these early-stage cells remained highly sensitive to IFNγ and IL6 stimulation and showed increased susceptibility to STAT1 inhibition by fludarabine, a sensitivity that was lost in resistant cells. Conclusions: Early enzalutamide treatment enhances immune responsiveness, while the development of resistance is associated with suppressed immune signaling and increased lineage plasticity. These results suggest a therapeutic window where combining enzalutamide with STAT inhibitors may delay or prevent lineage plasticity and resistance. Full article

The early stages of plant–microbe interaction are critical for establishing beneficial symbioses. We investigated how the endophytic fungus Fusarium solani strain FsK modulates tomato (Solanum lycopersicum) development and hormone pathways during in vitro co-cultivation. Seedlings were sampled at three early interaction stages (pre-contact, T1; initial contact, T2, 3 days post-contact, T3). Root traits and root and leaf transcripts for abscisic acid (ABA) and ethylene (ET) pathways were quantified, alongside fungal ET-biosynthesis genes. FsK altered root system architecture, increasing root area, lateral root number, root-hair length, and fresh biomass. These morphological changes coincided with tissue- and time-specific shifts. In leaves, FsK broadly affected ABA biosynthetic and homeostasis genes (ZEP1, NCED1, ABA2, AAO1, ABA-GT, BG1), indicating reduced de novo synthesis with enhanced deconjugation of stored ABA. ET biosynthesis was curtailed in leaves via down-regulation of ACC oxidase (ACO1–3), with isoform-specific changes in ACC synthase (ACS). The ET receptor ETR1 was transiently expressed early (T1–T2). FsK itself showed staged activation of fungal ET-biosynthesis genes. These results reveal coordinated fungal–plant hormone control at the transcriptional level that promotes root development during early interaction and support FsK’s potential as a biostimulant. Full article

The signal transducer and activator of transcription 3 (STAT3) in myeloid cells suppresses proinflammatory cytokine production and reduces collagen deposition. However, its role in methionine- and choline-deficient (MCD) diet-fed mice remains unclear. This study investigates the effects of myeloid-specific STAT3 deficiency on hepatic inflammation and fibrosis in MCD diet-fed mice. Myeloid-specific STAT3 knockout (mSTAT3KO) mice were fed the MCD diet for four weeks to induce metabolic dysfunction-associated steatohepatitis (MASH). MCD diet-fed mice displayed MASH-like pathological phenotypes, including hepatic steatosis, inflammation, and fibrosis. Compared with MCD diet-fed WT mice, mSTAT3KO mice fed the MCD diet exhibited reduced hepatic lipid accumulation but increased fibrosis. Notably, mSTAT3KO mice showed elevated hepatic STAT3 and lipocalin-2 (LCN2) protein levels in hepatocytes. Some proinflammatory cytokines were increased by the MCD diet in mSTAT3KO mice, which also exhibited increased hepatocyte apoptosis. Conversely, MCD diet-induced CD36, perilipin-2, acyl-CoA thioesterase 2, and 4-hydroxynonenal proteins were reduced by mSTAT3KO. Myeloid-specific STAT3 deficiency may induce a compensatory STAT3/LCN2 axis in hepatocytes, thereby exacerbating MASH progression. Full article

People Who Use Substances (PWUS) are among the most stigmatised groups in society. Stigma associated with substance use is known to be detrimental to the individual’s wellbeing, and substance use is often used as a mechanism by policy makers and services to legitimise exclusion. PWUS often do not benefit from the drug and alcohol services that are available to them. Community Asset Mapping (CAM) is a strengths-based approach involving the re-engagement of communities through active involvement in research. There are criticisms and concerns about equity and the burden on participants involved in CAM projects; however, the broad aim of CAM is to identify and document the strengths and pre-existing resources that exist within a community. In the following study, we utilised CAM processes and principles in a large city in the Northeast of England to enable people with lived experience of substance use and practitioners working in drug treatment services to come together and identify resources in the form of services and groups that support recovery. In the process, we were concerned with identifying, engaging with, and involving groups that were known to the recovery community but also were not part of an existing recovery network. Qualitative data were obtained from semi-structured interviews (n = 13) and focus groups (n = 2). A reflexive thematic analysis approach was used to analyse the transcriptions, and from this we generated four themes: (1) community visibility, (2) ownership of the recovery agenda, (3) the impact of stigma and shame, and (4) the benefits of involvement. Our findings revealed a partly fragmented but also well-established, connectedand resourced local recovery community in the city. We were also able to identify a number of recovery groups and services that had previously not been known to the existing recovery community. Additionally, we identified that public and societal substance-related stigma continued to be a barrier that inhibited individuals and recovery groups from making themselves more visible and available to others. Full article

Acacetin, a naturally occurring flavonoid, has attracted increasing attention due to its broad anticancer potential. In vitro and in vivo studies using diverse tumor models have demonstrated that acacetin modulates oncogenic signaling, suppresses angiogenesis, and induces apoptosis and other regulated cell death pathways. With the rising demand for multi-target therapeutics, network pharmacology and molecular docking have emerged as powerful tools to unravel the complex molecular mechanisms of phytochemicals. Unlike previous reviews that have mainly focused on single pathways or limited cancer contexts, this review emphasizes novelty by integrating network pharmacology with molecular docking and explicitly linking these computational predictions to experimental validation, thereby identifying epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), and the serine/threonine kinase AKT (also known as protein kinase B (PKB) as central experimentally supported targets. This integrative framework maps acacetin’s multi-target anticancer mechanisms and clarifies its translational opportunities for future therapeutic development. Full article

The invertebrate neuropeptide F (NPF) signaling plays versatile roles in diverse biological activities and processes. Still, whether and how it mediates feeding and digestion in Pomacea canaliculate remain gaps in our knowledge. Herein, we first identified and characterized PcNPFR via bioinformatics analysis in P. canaliculate, which is a polyphagous herbivore with a voracious appetite that causes devastating damages to ecosystem functioning and services in colonized ranges. Double stranded RNA (dsRNA)-based RNA interference (RNAi) and exogenous rescue were utilized to decipher and substantiate underlying mechanisms whereby NPFR executed its modulatory functions. Multiple sequence alignment and phylogeny indicated that PcNPFR harbored typical seven transmembrane domains (7 TMD) and belonged to rhodopsin-like GPCRs, with amino acid sequence sharing 27.61–63.75% homology to orthologues. Spatio-temporal expression profiles revealed the lowest abundance of PcNPFR occurred in pleopod tissues and the egg stage, while it peaked in male snails and testes. Quantitative real-time PCR (qRT-PCR) analysis showed that 4 µg dsNPFR and 10⁻⁶ M trNPF (NPFR agonist) were optimal doses to exert silencing and rescue effects, accordingly with sampling time at 3 days post treatments. Moreover, the dsNPFR injection (4 µg) at 1/3/5/7 day/s delivered silencing efficiency of 32.20–74.01%. After 3 days upon dsNPFR knockdown (4 µg), mRNA levels of ILP7/InR/Akt/PI3Kc/PI3K_R were significantly downregulated compared to dsGFP controls, except FOXO substantially upregulated at both transcript and translation levels. In addition, the activities of alpha-amylase, protease and lipase were significantly suppressed, accompanied by decreased leaf area consumption, attenuated feeding behavior and diminished feeding rate. Moreover, expression trends were opposite and proxies were partially or fully restored to baseline levels post exogenous compensation of trNPF, suggesting phenotypes specifically attributable to PcNPFR RNAi but not off-target effects. PcNPFR is implicated in both feeding and digestion by modulating the ISP pathway and digestive enzyme activities. It may serve as a promising molecular target for RNAi-based antifeedants to manage P. canaliculate invasion. Full article

Polynucleotide (PN), a high-molecular-weight DNA fragment derived from salmon and other fish sources, shows promising anti-aging and regenerative effects on the skin. This study investigated how PN enhances collagen synthesis, focusing on its effect on phosphoenolpyruvate carboxykinase 1 (PCK1) in senescent macrophages and its downstream effects on fibroblasts. Using in vitro senescent cell models and in vivo aged animal models, PN significantly upregulated the adenosine 2A receptor (A2AR), adenylate cyclase (AC), cyclic AMP (cAMP), protein kinase A (PKA), and cAMP response element-binding protein (CREB) in senescent macrophages. This led to increased PCK1 expression, which reduced oxidative stress and promoted M2 macrophage polarization, associated with elevated levels of interleukin-10 and tumor growth factor-β. Conditioned media from PN-treated macrophages enhanced SMAD family member 2 and signal transducer and activator of transcription 3 phosphorylation in senescent fibroblasts, increasing collagen I and III synthesis and reducing nuclear factor-κB activity. In vivo, PN administration elevated expression of the A2AR/AC/PKA/CREB/PCK1 pathway, reduced oxidative stress, increased M2 macrophage markers, and significantly improved collagen density and skin elasticity over time. Use of a PCK1 inhibitor attenuated these effects, highlighting the pivotal role of PCK1. Overall, PN modulates macrophage-fibroblast interactions via the CREB/PCK1 axis, enhancing collagen synthesis and counteracting age-related skin changes. PN has emerged as a promising therapeutic agent for skin rejuvenation by targeting cellular senescence and promoting extracellular matrix restoration. Full article

Background: Urban loneliness is rising worldwide and is a recognised public-health threat. Nature-Based Social Prescriptions (NBSPs), guided group activities in natural settings, are being piloted in six cities through the EU project RECETAS. However, in new contexts such as Marseille, its implementation is constrained by professionals’ limited knowledge of the concept. Objectives: (i) Exploring how professionals in Marseille (France) conceptualise NBSPs; (ii) Identifying perceived facilitators and barriers to implementing NBSPs among residents facing social isolation and loneliness. Methods: Twelve semi-structured interviews were conducted with health, social-care, and urban–environment professionals selected via network mapping and snowball sampling. Verbatim transcripts underwent inductive thematic analysis informed by Social Representation Theory, with double coding to enhance reliability. Results: Five analytic themes emerged: (1) a holistic health paradigm linking nature, community, and well-being; (2) stark ecological inequities with limited green-space access in deprived districts; (3) work challenges due to the urgent needs of individuals facing significant socio-economic challenges in demanding contexts; (4) a key tension between a perceived top-down process and a preference for participatory approaches; (5) drivers and obstacles: strong professional endorsement of NBSPs meets significant systemic and institutional constraints. Conclusions: Professionals endorse NBSPs as a promising approach against loneliness, provided programmes tackle structural inequities and adopt participatory governance. Results inform the Marseille RECETAS pilot and contribute to global discussions on environmentally anchored health promotion. Full article

Acute lymphoblastic leukemia (ALL) remains a formidable therapeutic challenge, particularly within high-risk cohorts. Advances in next-generation sequencing have elucidated critical mutations that significantly influence prognosis and therapeutic decision-making. Tyrosine kinase inhibitors (TKIs) have significantly improved treatment outcomes in Philadelphia chromosome-positive (Ph+) ALL. Meanwhile, emerging therapies such as monoclonal antibodies and chimeric antigen receptor (CAR) T-cell therapies show promise for B-cell ALL, although they are associated with considerable toxicities. These developments underscore the persistent need for alternative therapeutic strategies that can benefit a wider range of patients. In this study, human ALL cell lines—characterized by either wild-type or mutant tumor protein p53 (TP53) status—were treated with RG7388 (an MDM2 (mouse double minute 2 homolog) inhibitor) and BBI608 (a STAT3 (signal transducer and activator of transcription 3) inhibitor), both as single agents and in combination. Cell viability was quantified using XTT assays, while apoptosis was assessed via flow cytometry. Additionally, immunoblotting and qRT-PCR were employed to evaluate changes in protein and gene expression, respectively. RG7388 demonstrated potent growth inhibition in the majority of ALL cell lines, with p53-mutant cell lines exhibiting resistance. BBI608 reduced cell viability across all tested cell lines, though with variable sensitivity. Notably, the combination of RG7388 and BBI608 elicited synergistic anti-proliferative effects in p53 wild-type and partially functional p53-mutant cells, enhancing apoptosis and stabilizing p53 protein levels. In contrast, MOLT-4 cells, which harbor concurrent TP53 and STAT3 mutations, did not benefit from the combination treatment, indicating an inherent resistance phenotype within this subset. Collectively, these findings highlight the therapeutic potential of combined MDM2 and STAT3 inhibition in ALL, particularly in p53 wild-type and partially functional p53-mutant contexts. This combinatorial approach augments apoptosis and tumor growth suppression, offering a promising avenue for expanding treatment options for a broader patient population. Further investigation is warranted to validate these preclinical findings and to explore translational implications in genetically diverse ALL subsets. Full article