Throughout human history, several pandemics have caused the deaths of millions of people worldwide. The recent emergence of highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants underscores the urgent need for effective measures to protect surfaces from viral transmission to restrict the spread of coronavirus disease 2019 (COVID-19) infection. However, the absence of long-lasting antiviral materials in combating the COVID-19 pandemic is clearly necessitating constant surface disinfection, which in turn lies on small molecule-based surface decontamination. Herein, a combinatorial synthesis library of novel antiviral oligomers containing both N-halamine and quaternary ammonium functionalities with long-lasting bleaching properties to combat the spread of SARS-CoV-2 (including wild type, XBB1.5 and JN.1 variants) and the seasonal influenza virus (H1N1) is reported. Compared to household bleach, the most active oligomers exhibit superior antiviral activity that achieve over 99.8% efficacy against SARS-CoV-2 spikes at significantly lower concentrations. Additionally, the leading oligomers demonstrate rapid deactivation of the viruses and maintain superior activity (4 to 5 log reduction in viral copies) compared to household bleach on various surfaces for extended periods. Moreover, these oligomers are non toxic toward human lung epithelial cells and human keratinocytes, highlighting their potential as safe and efficient disinfection alternatives for future viral pandemics.

Glioblastoma is the most malignant and treatment-resistant primary brain tumor, driven by extensive cellular plasticity, epithelial-mesenchymal transition (EMT), and extracellular matrix (ECM) remodeling. Heat shock protein 27 (HSP27) stabilizes oncogenic signaling complexes and activates matrix metalloproteinases MMP-2 and MMP-9, facilitating invasion and metastasis. We implemented a structure-based high-throughput screening of FDA-approved compounds to identify inhibitors targeting HSP27-MMP-2/9 crosstalk. In silico studies have identified paroxetine, a selective serotonin reuptake inhibitor, as a high-affinity ligand for HSP27, inducing conformational destabilization and compromising its chaperone activity. Research on LN18 and LN229 glioblastoma cell lines showed that paroxetine treatment decreased cell viability and migration and lowered the levels of HSP27, MMP-2, and MMP-9. The C6 glioma rat model further confirmed the suppression of HSP27 and its crosstalk partner MMP-2/9 in tumor tissue. Collectively, these findings establish paroxetine as a functional HSP27 inhibitor that disrupts the interaction between HSP27 and MMP-2/9, thereby inhibiting glioblastoma progression.

Glioblastoma (GBM) is recognized as one of the most treatment-resistant malignancies, owing to its reinforced DNA repair systems and limited drug accessibility across the blood-brain barrier. This study, identifies, daidzin (DZN), a naturally derived isoflavone, as a potent redox-active DNA intercalator that intrinsically combines physical intercalation with chemical reactivity to breach this resistance. Unlike traditional intercalators, DZN autonomously triggers destabilization of DNA helices by inducing torsional strain, thereby producing convergent strand and base lesions through photo-independent redox pathways involving deoxyribose cleavage and C8 guanine oxidation. Additionally, DZN demonstrates pronounced glioma-specific cytotoxicity by initiating 1O2-driven oxo-cation formation and concomitant H2O2 production. This redox burst results in DNA strand scission activating robust DDR signaling and oxidative base lesions, which cripple tumor survival. Enhanced membrane fluidity in glioma cells likely facilitates superior DZN permeability, intracellular accumulation, thereby allowing DZN to initiate this robust DNA damage responses, culminating in G1 arrest and apoptosis in GBM cells while sparing normal glia. In vivo, DZN markedly suppresses tumor growth and surpasses temozolomide efficacy, current clinical option for GBM treatment. This work, thus, establishes a previously unrecognized paradigm of DNA intercalation-driven redox chemistry, presenting DZN as a promising therapeutic capable of exploiting the genomic frailties to overcome therapeutic resistance in glioma.

Manganese-based nanomaterials have emerged as highly promising candidates for cancer theranostic owing to their unique multifunctional capabilities in chemodynamic therapy, immune regulation, and magnetic resonance imaging (MRI). Herein, we present a biodegradable and multifunctional nanotherapeutic platform constructed by encapsulating manganese-doped carbon dots (MnCDs) within the zinc-based metal-organic framework (MOF)-ZIF-8 and further embedding the composite into a K-Carrageenan (K-Car) biopolymeric hydrogel matrix, referred to as the MnCD@ZIF-8@K-Car gel. This nanoplatform was designed for the efficient encapsulation of the anticancer drug 5-fluorouracil (5 FU) and exhibited a pronounced pH-responsive drug release profile under tumor-mimicking acidic conditions. The MnCD@ZIF-8@K-Car system demonstrated intense blue fluorescence, enabling effective in vitro fluorescence imaging, and exhibited excellent T1-T2-weighted MRI contrast enhancement at low concentrations. Moreover, the nanocomposite catalyzed Fenton-like reactions with endogenous hydrogen peroxide in the microenvironment, producing highly reactive hydroxyl radicals that induce oxidative damage to intracellular biomolecules and suppress tumor cell proliferation. In addition, the ZIF-8 imparted notable bacteriostatic activity against Gram-negative Escherichia coli. Cellular internalization and cytotoxicity investigations revealed selective toxicity toward folate-receptor-overexpressing HeLa cells, while comparatively reduced cytotoxic effects were observed in MDA-MB-231 breast cancer cells and nonmalignant L929 fibroblasts. Overall, this multifunctional MnCD@ZIF-8@K-Car nanohydrogel integrates pH-responsive chemotherapy, chemodynamic therapy, biosensing, dual-modal imaging, and antibacterial functionality within a single system, highlighting its strong potential for advanced cancer theranostic applications.

Abstract Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor, characterized by rapid progression, high recurrence rates, and a median survival of less than 15 months despite current therapeutic interventions. Standard treatments such as surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy offer limited benefit due to the infiltrative nature of the tumor and the blood-brain barrier. Moreover, GBM frequently develops resistance to TMZ through O6-methylguanine-DNA methyltransferase (MGMT)-mediated repair of chemotherapy-induced DNA damage, significantly reducing treatment effectiveness. During treatment, GBM cells and the surrounding tumor microenvironment (TME) undergo significant physiological stress, including hypoxia, inflammation, and DNA damage. These stressors induce the release of damage-associated molecular patterns (DAMPs), among which High Mobility Group Box 1 (HMGB1) plays a pivotal role. HMGB1 is a multifunctional nuclear protein that, depending on its redox state and subcellular localization, can regulate tumor proliferation, invasion, angiogenesis, and immune modulation. Accumulating evidence suggests that extracellular HMGB1 contributes to tumor progression and therapeutic resistance through complex interactions with immune and stromal components of the TME. In our present study, we aim to validate the protumorigenic functions of HMGB1 using integrated bioinformatic approaches and in vitro analyses to substantiate its relevance in GBM pathology and therapy resistance. Specifically, we explored the correlation between HMGB1 expression and TMZ resistance, examining its association with MGMT expression and the activation of downstream signaling pathways, such as MEK1/2-ERK1/2. By elucidating these molecular interactions, we aim to clarify the mechanisms through which HMGB1 promotes therapy resistance. Additionally, we performed in-silico screening to identify HMGB1-targeting inhibitory compounds with the potential to concurrently suppress MGMT expression and other crucial components involved in TMZ resistance. Collectively, our findings aim to reinforce the significance of HMGB1 as a prognostic biomarker and therapeutic target, offering new opportunities for more effective and personalized treatment strategies for GBM patients. Citation Format: Sucharita Patra, Shreya Banerjee, Mahitosh Mandal, . HMGB1 mediates chemoresistance and tumor progression in glioblastoma: Implications for targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3184.

Chemoresistance poses a significant challenge while treating triple-negative breast cancer, and cancer stem cells are one of the key regulators of chemoresistance in breast cancer. SOX2, a crucial regulator of pluripotency in breast cancer stem cells, has been associated with poor prognosis and therapeutic resistance. Breast cancer stem cells can evade chemotherapy by modulating DNA damage pathways and altering cell cycle regulation. However, how SOX2 is linked with these pathways is largely unknown, which is the primary focus of our study. Overexpression clones were established for cell lines with low SOX2 expression to conduct gain-of-function experiments, while loss-of-function studies were performed on high SOX2-expressing lines using SOX2 silencer RNA (siRNA). SOX2 overexpression in breast cancer enhanced migration, sphere formation, and chemoresistance, while SOX2 knockdown inhibited these processes. Similar effects were observed on the expression of drug efflux proteins (ABCB1, ABCC1, ABCG2). Flow cytometry analysis revealed significant changes in the proportion of cells in the G2/M phase when SOX2 was overexpressed or knocked down, both in the presence and absence of doxorubicin, at varying doses. Immunoblotting confirmed that SOX2 overexpression induced a G2/M cell cycle arrest, as well as DNA damage response and repair. In nude mice, SOX-2 overexpression resulted in an enhanced capacity to form breast cancer tumors compared with the empty vector control. These findings illustrated that targeting SOX2 could be a promising strategy for overcoming chemoresistance in breast cancer. Overall, this study suggests that targeting SOX2 may be an effective strategy for overcoming chemoresistance in breast cancer.

ABSTRACT Ferroptosis is a redox‐governed, non‐apoptotic cell death program driven by iron‐dependent lipid peroxidation. Its execution depends on the balance between reactive oxygen species (ROS) generation and hierarchical antioxidant defenses. Despite extensive biochemical mapping, an integrated framework delineating how diverse redox defense systems converge to dictate ferroptotic sensitivity across tumor contexts remains lacking. This review delineates the hallmarks and molecular mechanisms of ferroptosis, examining how ROS sources within mitochondrial, the endoplasmic reticulum, membranes, and the cytoplasm drive lipid peroxidation. The antioxidant landscape is systematically classified into three functional tiers: (1) the primary canonical glutathione‐GPX4 axis, (2) secondary non‐canonical and radical‐trapping systems including FSP1‐CoQ10, GCH1‐BH4, peroxiredoxins, and vitamin K, and (3) tertiary metabolic support and detoxification systems encompassing thioredoxin, AKR1C enzymes, SOD‐catalase, and NADPH regeneration. The regulation of these defenses by master signaling hubs including NRF2, AMPK‐mTOR, ATF4, STAT3, Wnt/beta‐catenin, p53, and ncRNAs is evaluated, alongside oncogenic metabolic adaptations creating exploitable vulnerabilities in high‐plasticity states including epithelial to mesenchymal transition, cancer stem cells, hypoxic, matrix‐detached, and chemoresistant cells. Tumor microenvironment crosstalk among cancer‐associated fibroblasts and immune effectors, including CD8 + T cells, natural killer cells, macrophages, and myeloid‐derived suppressor cells, and therapeutic strategies spanning pharmacological and nanomaterial‐based approaches are further examined. Collectively, this synthesis furnishes a mechanistic framework for precision exploitation of ferroptosis across oncological contexts.

Reactive oxygen species (ROS) are chemically reactive oxygen derived molecules generated as unavoidable byproducts of metabolism and tightly regulated enzymatic reactions. Under physiological conditions, moderate ROS levels generate oxidative eustress that supports essential signaling functions, enabling cellular communication, metabolic regulation, immune defense, and adaptive stress responses. Beyond the cell-autonomous level, ROS function as critical systemic messengers that facilitate organ-organ communication, coordinating integrated physiological responses across distal tissues to maintain organismal homeostasis. Disruption of the balance between ROS production and antioxidant buffering capacity leads to redox imbalance or oxidative distress, resulting in oxidative modification of lipids, proteins, nucleic acids, and organelles and driving pathological outcomes. Importantly, ROS do not act solely as damaging agents but actively modulate major signaling pathways including NF-κB, MAPKs, PI3K/AKT, NRF2, HIF-1α, and Wnt/β-catenin, thereby shaping inflammation, metabolism, survival, and cell fate decisions. When redox control is lost, excessive ROS engage multiple regulated oxidative cell death programs such as apoptosis, ferroptosis, necroptosis, pyroptosis, paraptosis, parthanatos, oxeiptosis, and NETosis, each governed by distinct redox sensitive mechanisms. This failure of redox coordination underlies a broad spectrum of diseases, including cancer, neurodegenerative disorders, cardiovascular disease, and diabetes. Collectively, these insights position redox organization, rather than bulk oxidative stress, as the critical determinant of signaling integrity, cell fate, and disease vulnerability, and as a key focus for future therapeutic innovation.

Ir(III)-based metallo-anticancer complexes offer promising therapeutic strategies with their efficacy fine-tuned through structural modifications, leveraging multitargeted mechanisms of action to reduce resistance compared to traditional chemotherapeutics. Herein, we report a photoactive Ir(III)-complex [Ir-biotin] designed with an ion-chelating ancillary ligand to disrupt copper homeostasis and simultaneously induce oxidative stress, aiming to overcome chemotherapeutic drug-resistance in pancreatic cancer. The complex features a nonsymmetrical polytopic ligand covalently linked to phenanthroline and imidazole-quinoline fragments, with a biotin tag for targeted delivery and an open N^N-coordination site for cellular ion interactions. Ir-biotin exhibits potent micro- to nanomolar-level therapeutic efficacy against MIAPaCa-2 and PANC-1 cells under dark and light conditions. We observed that ferroptosis-inducing Ir-biotin significantly downregulated glutathione peroxidase 4 (GPX4) expression, leading to increased lipid peroxidation (LPO) accumulation. Collectively, mechanistic investigations reveal that Ir-biotin translocates into the mitochondria, preferentially coordinates with mitochondrial Cu-ions, and induces a significant increase in reactive oxygen species (ROS), lipid peroxidation (LPO) in the cell membrane, and photoregulated oxidase-mimicking activity. Ir-biotin synergistically triggers apoptosis-linked ferroptosis and therefore represents a promising candidate for overcoming drug resistance via chemo-photodynamic tumor therapy.

This abstract describes a novel, stimulus-responsive drug delivery system for cancer therapy, emphasizing a biodegradable, targeted approach to minimize side effects. The system utilizes a Fe-based metal organic coordination gel (MOG) with a porous structure, designed for high-capacity drug loading and Fenton reaction facilitation to destroy cancer cells. The MOG, synthesized via a simple, eco-friendly method, demonstrates peroxidase-like behavior under visible light, enhancing Fenton-type reactions. Carbon dots (CDs), produced through a hydrothermal process, are incorporated for bio-imaging and tracking, while the anti-cancer drug 5 Fluorouracil (5 FU) is loaded with a high capacity of 72.9 %. This system ensures controlled drug release in acidic environments, reducing premature leakage and side effects on healthy cells. A 450 nm light source enhances Fe²⁺ stability, where Fe³⁺ released in acidic cancerous environments converts to Fe²⁺ by photo reduction process and reacts with cellular H₂O₂, producing hydroxyl radicals (HO•) that oxidize critical cellular components, inhibiting cancer growth. Cellular uptake and cytotoxicity were evaluated in various cell lines, with MTT assays revealing selective toxicity to folate-positive HeLa cancer cells, showing reduced effects on comparatively less folate-positive MDA-MB-231 cells and non-cancerous L929 cells. This innovative approach combines pH-responsive chemo-photodynamic therapy with bio-sensing and imaging in one platform, demonstrating significant promise in advanced cancer treatment applications.

Breast cancer, with its diverse subtypes like ER-positive, HER-2-positive, and triple-negative, presents complex challenges demanding personalized treatment approaches. The intricate interplay of genetic, environmental, and lifestyle factors underscores its status as a primary contributor to cancer-related fatalities in women globally. Understanding the molecular drivers specific to each subtype is crucial for developing effective therapies. In this landscape, connective tissue growth factor (CTGF), also referred to as cellular communication network factor 2 (CCN2), emerges as a significant player. CTGF regulates critical biological activities like cell growth, invasion, and migration, impacting breast cancer development and progression. It modulates breast tumor microenvironment by promoting angiogenesis, activating cancer-associated fibroblasts (CAFs), and inducing inflammation. The activity of CTGF depends on several factors including oxygen levels, hormone signals, and growth factors and differs according to the type of breast cancer. CTGF can regulate breast cancer cells by activating various signaling pathways and modulating the transcription of other genes that are involved in tumor development and metastasis including S100A4, glucose transporter 3 (GLUT3), and vascular endothelial growth factor (VEGF). The matricellular protein can be considered a potential therapeutic target, as it can promote tumor growth and confer drug resistance in breast cancer. Numerous tactics, including neutralizing antibodies, antisense oligonucleotides, natural compounds, recombinant proteins, and short hairpin RNAs have been suggested to block its function. This review highlights the structure of CTGF, regulation of its expression, and current knowledge of its oncogenic role in breast cancer, as well as focusing on potential therapeutic strategies for targeting CTGF in breast cancer.

Developing multifunctional smart luminescent hydrogel materials has recently garnered tremendous interest. Nevertheless, most of the reported luminescent hydrogels fail to adequately satisfy the criteria for both robust mechanical characteristics and smart luminescence. This study reports smart luminescent hydrogels with enhanced mechanical properties through Laponite clay-incorporated in situ lanthanide ion cross-linked co-polymerization of acrylamide, 2-acrylamido-2-methylpropane sulfonic acid (AMPS), and terpyridine-based hydrophobic acrylic co-monomer as lanthanide sensitizer and to promote hydrophobic association. The addition of Laponite clay resulted in significant enhancement of luminescence within the hydrogel matrix and superior mechanical properties. A synergistic combination of electrostatic interaction, hydrophobic association, and metal-ligand interaction helped to achieve tensile strength of ≈330 kPa, high flexibility (fracture strain of 1110%), and toughness (≈1.8 MJ m-3). The ionically conducting (4.54 mS cm-1) hydrogel is further utilized for demonstrating a flexible human motion sensor and communicator for speech disability. The stimuli-responsive behavior and multi-color luminescence of the hydrogel are exploited to demonstrate potential application for anti-counterfeiting through ASCII Code and QR code, and to construct a logic system using single-input logic operation (NOT, PASS1) and double-input logic operation (OR, IMPLY), which may have significant potential in the field of multicolor pattern anti-counterfeiting and information encryption.

Monitoring H2O2 levels in live cells is essential due to its superior stability and possible severity inside the cell. The quest for a superior platform capable of detecting cellular-level hydrogen peroxide (H2O2) concentrations without necessitating the use of high-cost enzymes is of utmost importance. Here, the quantification of intracellular H2O2 concentrations has been performed using silver metal polymer-based nonenzymatic electrochemical detection. Two forms of silver metal-organic polymers are synthesized to explore its suitability as catalytic nanozyme activity for cell-level H2O2 detection with good accuracy. An Ag-O coordination interactionbased silver metal-organic framework, AgMOF-5 was synthesized and then transformed into a compact silver nanosphere (Ag nanosphere), rich in Ag-N coordination bond, to find the potential of individual coordination arrangement of each material in favour of the electrical conductivity, catalytic property, and sensing ability. AgMOF-5 modified Glassy Carbon Electrode (AgMOF/GCE) was found to be highly conductive while also demonstrating exceeding catalytic potential towards both commercial H2O2 and cell-secreted H2O2 with a LOD of 0.7 nM and sensitivity of 1300 mu A mM- 1cm- 2. AgMOF/GCE demonstrated superior sensor characteristics like superconductivity, high stability, high reproducibility, and good selectivity upon investigation. Among many cellular byproducts of metabolism, H2O2 and other ROS species indicate the oxidative stress and are a key differentiator between healthy and diseased conditions. The modified GCE was used for live monitoring of H2O2 levels in L929, HeLa, T98G, and LN18 cell lines. The detection of higher H2O2 levels in glial cells established its predisposition towards increased oxidative stress. The electrochemical results of AgMOF/GCE were validated against a Phenol Red, HRPO-based live cell compatible Colourimetric detection for applicability and acceptance of AgMOF/GCE as H2O2 detection platform.

The favorable success rate in cancer treatment predominantly depends on precise diagnosis with target-specific drug delivery, which can regulate the patient survival outcome rate. Moreover, proper tracking of the system's pH is very much crucial as most of the therapeutic's action and release rate depend on it. Therefore, this work has been intended to fabricate a folic acid-derived carbon dot (FACD) decorated with chitosan (Cs) in order to form nanospheres (FACD-Cs-Ns) for anticancer doxorubicin hydrochloride (Dox.HCl) drug delivery through imaging in cancer therapeutic treatment. The engineered FACD-Cs-Ns demonstrated a spherical shape with an extensive surface area, rich in carboxyl and hydroxyl groups that play a key role in its pH-responsive characteristics through protonation and deprotonation interactions. Thanks to their impressive fluorescence traits and excellent stability, FACD-Cs-Ns are particularly well suited for imaging-guided cancer therapy. Their remarkable cytocompatibility with normal cells and significant toxicity toward cancer cells, along with pH-responsive properties, render them as ideal candidates for targeted drug delivery to cancer cells. The G2/M and S phases' arrest in the cell cycle analysis study once more validated excellent in vitro experimental conditions. The impressive selectivity and cytotoxicity of Dox-loaded FACD-Cs-Ns toward cancer cells can be attributed to enhanced cellular uptake via folate-receptor-mediated endocytosis, which is overexpressed in these cells. These findings elucidate that the FACD-Cs-Ns nanoprobe is an excellent material for pH-responsive anticancer drug delivery and image-guided cancer therapy.

Antineoplastic drug-conjugated pH-responsive polymeric nanoparticles have attracted much attention because of their efficacy in killing carcinoma cells with minimum side effects on normal cells. In the present work, we have synthesized an amphiphilic block copolymer Poly(PEGMA-b-DOPMA) to formulate a pH-responsive biocompatible polymeric prodrug system (PDBD) having antineoplastic drug doxorubicin (DOX) conjugated to the polymeric side chain through 4-formylphenylboronic acid. The self-assembly behavior, pH-responsive structural changes, drug loading content, and controlled in-vitro release of DOX from PDBD nanoparticles in both physiological and acidic conditions were studied using dynamic light scattering, fluorescence spectroscopy, UV-vis spectroscopy, and transmission electron microscopy. The synthesized prodrug nanoparticles were also evaluated for their in vitro toxicity, uptake efficiency, and pH-responsive activities against breast cancer cell lines. In MTT assay, the PDBD nanoparticles were found to have a significantly lower IC50 value against MCF-7 cancer cells in comparison to free DOX. The cytotoxic effects of the nanoparticles on cancer cells were also evident from the morphological distortion of the MCF-7 cells revealed in phase contrast microscopy images. Efficient cellular uptake followed by pH-responsive drug release was also monitored in the MCF-7 cancer cells by fluorescence microscopy, indicating these prodrug nanoparticles to be potent nanocarrier systems for cancer therapy.

Leishmania donovani (Ld), the etiological agent of visceral leishmaniasis, poses a significant global health burden due to its complex dixenous lifecycle involving both insect vectors and mammalian hosts. Successful infection in mammals requires the coordinated activity of stage-specific virulence factors. The zinc metalloprotease glycoprotease 63 (GP63) is a well-established virulence determinant critical for host cell attachment and invasion by insect-stage promastigotes. For humans, subsequent parasite propagation depends exclusively on intracellular amastigotes arising from lysed macrophages. Classical GP63 expression and function in Ld amastigotes remain poorly understood, and GP63 null mutants reportedly retain infectivity in mice, raising fundamental questions about virulence factor complementation during mammalian infection. By employing comparative transcriptomics, CRISPR-based mutagenesis, complemented with cell biology, and biochemical assays, this work identifies and characterizes multiple Ld GP63 paralogues with distinct roles in mammalian infection. While both copies of GP63 encoded on chromosome 10 (LdGP63\_10.51 and 10.52) were functionally redundant, LdGP63\_28 encoded on chromosome 28 proved essential for intracellular amastigote survival by suppressing host cell pyroptosis. Moreover, LdGP63\_31 (chromosome 31) was found to primarily mediate promastigote attachment to the host macrophages with minimal contribution from LdGP63\_28, facilitating initial infection establishment and amastigote genesis. Importantly, the absence of LdGP63\_28 impacted amastigote infection more severely as compared to LdGP63\_31. Structural and enzymatic analyses revealed divergent localization and substrate specificities to fulfil functional requirement of these divergent proteases, which have evolved independently to carry out diverse function in establishing infection. Collectively, this study indicates evolutionary divergence and functional specialization among GP63 isoforms in Ld by demonstrating that amastigote-specific and promastigote-specific GP63 isoforms synergistically mediate infection establishment and persistence. ### Competing Interest Statement The authors have declared no competing interest.

Glioblastoma multiforme (GBM), a grade IV brain tumor, remains one of the most aggressive and difficult-to-treat cancers, emphasizing the urgent need for novel therapeutic targets. The dysregulation of the unfolded protein response, particularly involving the proteasomal pathway, contributes significantly to the pathogenesis of GBM. Proteasome 26S subunit ATPase 2 (PSMC2) has recently been identified as a potential factor in carcinogenesis; however, the molecular mechanisms involved remain unclear. In this study, we found significantly high expression of PSMC2 in GBM, with increased levels associated with an unfavorable prognosis. PSMC2 knockdown in GBM cell lines reduced proliferation, impaired migration, and induced apoptosis, while its overexpression enhanced epithelial-to-mesenchymal transition (EMT) related marker expression. Further, the tumorigenic effect of PSMC2 was confirmed in vivo as PSMC2 knockdown reduced the tumor volume and weight. Mechanistically, PSMC2 promoted malignancy via nuclear localizing of β-catenin by activating AKT/GSK3β/β-catenin axis, with AKT-mediated inhibitory phosphorylation of GSK3β enabling β-catenin activation. Besides, we used Lithium chloride to induce GSK3β phosphorylation which reversed the effects of PSMC2 knockdown, further validating this pathway. These findings demonstrate that PSMC2 drives GBM progression by regulating the AKT/GSK3β/β-catenin axis, positioning it as a promising biomarker and therapeutic target for GBM.

Self-assembled micelles are popular as a nanoplatform for cancer therapeutics. However, they still suffer from several drawbacks, like lower drug loading capacity and premature drug release. In order to overcome these issues, we have presently developed new redox-responsive cross-linked micelles using lipoic acid-containing polymers, poly(NVP)-b-poly(LABPA). The self-assembly behavior of the polymers was monitored before and after cross-linking in the presence of a catalytic amount of glutathione (GSH). The core cross-linked (CCL) polymeric micelles were further subjected to high GSH concentrations found in cancer cells, and the corresponding de-cross-linking of the core, followed by an analogous size change, was investigated using dynamic light scattering (DLS) and AFM measurements. In comparison to precursor polymers, the higher drug (doxorubicin; DOX) loading capacity (DLC) of 24.5% of the CCL micelles and GSH-triggered rapid drug release suggested their importance as a potent drug delivery system for cancer therapy. Very often, a successful cancer treatment is inhibited by the drug resistance of the cancer cells. In this present work, the in vitro cytotoxicity study was performed using drug-sensitive and drug-resistant MDA-MB-231 cells, where a lower IC50 value of the drug-loaded CCL micelles was obtained in comparison to free DOX toward both drug-sensitive and resistant cells, justifying their potential utility in cancer therapeutics. Briefly, our lipoic acid-containing redox-responsive polymers, poly(NVP)-b-poly(LABPA), show significantly enhanced drug loading capacity (24.5%), wonderful extracellular stability with rapid GSH-triggered drug release in the intracellular redox environment, and importantly, the DOX-loaded CCL micelles show significantly lower IC50 values for both the parental and resistant cancer cells than free DOX, calling attention to their efficiency over other existing drug delivery vehicles.