A nanocomposite competent to overcome cascade drug resistance in ovarian cancer via mitochondria dysfunction and NO gas synergistic therapy

Ovarian cancer(OC)is one of the most common and recurring malignancies in gynecology.Patients with relapsed OC always develop"cascade drug resistance"(CDR)under repeated chemotherapy,leading to subsequent failure of chemotherapy.To overcome this challenge,amphiphiles(P1)carrying a nitric oxide(NO)donor(Isosorbide 5-mononitrate,ISMN)and high-density disulfide are synthesized for encapsulatingmitochondria-targeted tetravalent platinum prodrug(TPt)to construct a nanocomposite(INP@TPt).Mechanism studies indicated that INP@TPt significantly inhibited drug-resistant cells by increasing cellular uptake and mitochondrial accumulation of platinum,depleting glutathione,and preventing apoptosis escape through generating highly toxic peroxynitrite anion(ONOO−).To better replicate the microenvironmental and histological characteristics of the drug resistant primary tumor,an OC patient-derived tumor xenograft(PDXOC)model in BALB/c nude mice was established.INP@TPt showed the best therapeutic effects in the PDXOC model.The corresponding tumor tissues contained high ONOO−levels,which were attributed to the simultaneous release of O_(2)^(·−)and NO in tumor tissues.Taken together,INP@TPtbased systematic strategy showed considerable potential and satisfactory biocompatibility in overcoming platinum CDR,providing practical applications for ovarian therapy.

Triterpenoids-templated self-assembly nanosystem for biomimetic delivery of CRISPR/Cas9 based on the synergy of TLR-2 and ICB to enhance HCC immunotherapy

Combination immunotherapy has shown promising potential for enhancing the objective response rate compared to immune checkpoint blockade(ICB)monotherapy.However,combination therapy with multi-drugs is limited by the different properties of the agents and inconsistent synergistic targeted delivery.Herein,based on a universal triterpene template and the anticancer active agent ursolic acid(UA),a cytomembrane-coated biomimetic delivery nanoplatform(UR@M)prepared by the selfassembly of a PD-L1 targeted CRISPR/Cas9 system and UA was designed for hepatocellular carcinoma(HCC)treatment.UR@M showed enhanced tumor accumulation in vivo with homologous tumor targeting,and CRISPR in the nanosystem exhibited potent gene-editing efficiency of 76.53% in vitro and 62.42% in vivo with no off-target effects.UA activated the natural immune system through the TLR-2-MyD88-TRAF6 pathway,which synergistically enhanced the proliferation of natural killer cells and dendritic cells and realized excellent immune cytotoxic T cell infiltration by combining with the ICB of PD-L1.The strategy of work along both lines based on innate immune and adaptive immunity displayed a significant effect in tumor regression.Overall,the UA-templated strategy“killed three birds with one stone”by establishing a self-assembly nanosystem,inducing tumor cell death,and promoting synergistic immunostimulation for HCC treatment.

Luminescence-activated Pt(Ⅳ)prodrug for in situ triggerable cancer therapy

Anticancer platinum prodrugs that can be controllably activated are highly desired for personalized precision medicine and patient compliance in cancer therapy.However,the clinical application of platinum(Ⅳ)prodrugs(Pt(Ⅳ))is restricted by tissue penetration of external irradiation.Here,we report a novel Pt(Ⅳ)activation strategy based on endogenous luminescence of tumor microenvironment responsiveness,which completely circumvents the limitation of external irradiation.The designed Pt(Ⅳ)–Lu,a mixture of trans,trans,trans-[Pt(N_(3))_(2)(OH)_(2)(py)_(2)]and luminol(Lu),has controllable activation property:it remains inert in reductant environment and normal tissues,but under tumor microenvironment,Lu will be oxidized to produce blue luminescence,which rapidly reduce Pt(Ⅳ)to Pt(Ⅱ)without the need of any external activator.Pt(Ⅳ)–Lu shows excellent responsive antitumor ability both in vitro and in vivo.Compared to cisplatin,the median lethal dose in BALB/c mice increased by an order of magnitude.Our results suggest that Pt(Ⅳ)–Lu exhibits highly controllable activation property,superior antitumor activity,and good biosafety,which may provide a novel strategy for the design of platinum prodrugs.

The potential application of formulation with pimelic acid as eye drops for corneal collagen cross-linking

Background and aim:Keratoconus is a slowly progressive and non-inflammatory disease of eye of unknown etiology characterized by significant structural degeneration,thinning and protrusion of cornea.Collagen cross linking using Riboflavin/ultraviolet A,paraformaldehyde and glutaraldehyde has been widely used to treat keratoconus,but these techniques have several clinical complications.This study aimed to develop a rapid,safer,less toxic and more effective method to increase the corneal stiffness hence treating keratoconus by using EDC/NHS coupling with pimelic acid(PA)as cross-linkers.Methods:The viability of corneal epithelial and endothelial cells was examined using Alamar blue.The corneal collagen and tissue integrity were evaluated with Masson and hematoxylin and eosin stains respectively.Uniaxial tensile testing was conducted to determine the tissue stiffness.We further assessed the effective penetration depth of cross-linking by fluorescence dye and confocal microscopy.TUNEL assay was performed to detect the damaged DNA fragments in the presence of PA.Results:The effect of PA solution on corneal cross-linking showed a significant increase in corneal rigidity without affecting the epithelium integrity under neutralized pH condition,while DEC/NHS alone did not induce the mechanical property.The penetration depth showed consistent results with increased stiffness,which could be affected by the parameters including pH condition,coupling with or without PA.In addition,PA significantly decreased the percentage of TUNEL-positive cells compared to that of EDC/NHS only condition.The cytotoxic effect to endothelium was considered minimal and protected in the presence of PA.Conclusions:We demonstrated PA as a potential alternative for cross-linking in the model of whole eye with intact epithelium and its protective role on endothelium.The administration of this chemical cross-linker stands as an extremely promising technique for the treatment of corneal keratoconus.

An immunotherapeutic hydrogel booster inhibits tumor recurrence and promotes wound healing for postoperative management of melanoma

Low tumor immunogenicity,immunosuppressive tumor microenvironment,and bacterial infections have emerged as significant challenges in postsurgical immunotherapy and skin regeneration for preventing melanoma recurrence.Herein,an immunotherapeutic hydrogel booster(GelMA-CJCNPs)was developed to prevent postoperative tumor recurrence and promote wound healing by incorporating ternary carrier-free nanoparticles(CJCNPs)containing chlorine e6(Ce6),a BRD4 inhibitor(JQ1),and a glutaminase inhibitor(C968)into methacrylic anhydride-modified gelatin(GelMA)dressings.GelMA-CJCNPs reduced glutathione production by inhibiting glutamine metabolism,thereby preventing the destruction of reactive oxygen species generated by photodynamic therapy,which could amplify oxidative stress to induce severe cell death and enhance immunogenic cell death.In addition,GelMA-CJCNPs reduced M2-type tumor-associated macrophage polarization by blocking glutamine metabolism to reverse the immunosuppressive tumor microenvironment,recruiting more tumor-infiltrating T lymphocytes.GelMA-CJCNPs also downregulated IFN-γ-induced expression of programmed cell death ligand 1 to mitigate acquired immune resistance.Benefiting from the amplified systemic antitumor immunity,GelMA-CJCNPs markedly inhibited the growth of both primary and distant tumors.Moreover,GelMA-CJCNPs demonstrated satisfactory photodynamic antibacterial effects against Staphylococcus aureus infections,thereby promoting postsurgical wound healing.Hence,this immunotherapeutic hydrogel booster,as a facile and effective postoperative adjuvant,possesses a promising potential for inhibiting tumor recurrence and accelerating skin regeneration.

Engineering anti-thrombogenic and anti-infective catheters through a stepwise metal-catechol-(amine)surface engineering strategy

Thrombosis and infection are pivotal clinical complications associated with interventional blood-contacting devices,leading to significant morbidity and mortality.To address these issues,we present a stepwise metal-catechol-(amine)(MCA)surface engineering strategy that efficiently integrates therapeutic nitric oxide(NO)gas and antibacterial peptide(ABP)onto catheters,ensuring balanced anti-thrombotic and anti-infective properties.First,copper ions were controllably incorporated with norepinephrine and hexanediamine through a one-step molecular/ion co-assembly process,creating a NO-generating and amine-rich MCA surface coating.Subsequently,azide-polyethylene glycol 4-N-hydroxysuccinimidyl and dibenzylcyclooctyne modified ABP were sequentially immobilized on the surface via amide coupling and bioorthogonal click chemistry,ensuring the dense grafting of ABP while maintaining the catalytic efficacy for NO.This efficient integration of ABP and NO-generating ability on the catheter surface provides potent antibacterial properties and ability to resist adhesion and activation of platelets,thus synergistically preventing infection and thrombosis.We anticipate that this synergistic modification strategy will offer an effective solution for advancing surface engineering and enhancing the clinical performance of biomedical devices.

Tailoring therapeutics via a systematic beneficial elements comparison between photosynthetic bacteria-derived OMVs and extruded nanovesicles

Photosynthetic bacteria(PSB)has shown significant potential as a drug or drug delivery system owing to their photothermal capabilities and antioxidant properties.Nevertheless,the actualization of their potential is impeded by inherent constraints,including their considerable size,heightened immunogenicity and compromised biosafety.Conquering these obstacles and pursuing more effective solutions remains a top priority.Similar to extracellular vesicles,bacterial outer membrane vesicles(OMVs)have demonstrated a great potential in biomedical applications.OMVs from PSB encapsulate a rich array of bioactive constituents,including proteins,nucleic acids,and lipids inherited from their parent cells.Consequently,they emerge as a promising and practical alternative.Unfortunately,OMVs have suffered from low yield and inconsistent particle sizes.In response,bacteria-derived nanovesicles(BNVs),created through controlled extrusion,adeptly overcome the challenges associated with OMVs.However,the differences,both in composition and subsequent biological effects,between OMVs and BNVs remain enigmatic.In a groundbreaking endeavor,our study meticulously cultivates PSB-derived OMVs and BNVs,dissecting their nuances.Despite minimal differences in morphology and size between PSB-derived OMVs and BNVs,the latter contains a higher concentration of active ingredients and metabolites.Particularly noteworthy is the elevated levels of lysophosphatidylcholine(LPC)found in BNVs,known for its ability to enhance cell proliferation and initiate downstream signaling pathways that promote angiogenesis and epithelialization.Importantly,our results indicate that BNVs can accelerate wound closure more effectively by orchestrating a harmonious balance of cell proliferation and migration within NIH-3T3 cells,while also activating the EGFR/AKT/PI3K pathway.In contrast,OMVs have a pronounced aptitude in anti-cancer efforts,driving macrophages toward the M1 phenotype and promoting the release of inflammatory cytokines.Thus,our findings not only provide a promising methodological framework but also establish a definitive criterion for discerning the optimal application of OMVs and BNVs in addressing a wide range of medical conditions.

Bioinspired super-hydrophilic zwitterionic polymer armor combats thrombosis and infection of vascular catheters

Thrombosis and infection are two major complications associated with central venous catheters(CVCs),which significantly contribute to morbidity and mortality.Antifouling coating strategies currently represent an efficient approach for addressing such complications.However,existing antifouling coatings have limitations in terms of both duration and effectiveness.Herein,we propose a durable zwitterionic polymer armor for catheters.This armor is realized by pre-coating with a robust phenol-polyamine film inspired by insect sclerotization,followed by grafting of poly-2-methacryloyloxyethyl phosphorylcholine(pMPC)via in-situ radical polymerization.The resulting pMPC coating armor exhibits super-hydrophilicity,thereby forming a highly hydrated shell that effectively prevents bacterial adhesion and inhibits the adsorption and activation of fibrinogen and platelets in vitro.In practical applications,the armored catheters significantly reduced inflammation and prevented biofilm formation in a rat subcutaneous infection model,as well as inhibited thrombus formation in a rabbit jugular vein model.Overall,our robust zwitterionic polymer coating presents a promising solution for reducing infections and thrombosis associated with vascular catheters.

COX-2 blocking therapy in cisplatin chemosensitization of ovarian cancer:An allicin-based nanomedicine approach

Recently,the utilization of nonsteroidal anti-inflammatory drugs(NSAIDs)to sensitize cisplatin(CDDP)has gained substantial traction in the treatment of ovarian cancer(OC).However,even widely employed NSAIDs such as celecoxib and naproxen carry an elevated risk of cardiovascular events,notably throm-bosis.Furthermore,the diminished sensitivity to CDDP therapy in OC is multifactorial,rendering the ap-plication of NSAIDs only partially effective due to their cyclooxygenase-2(COX-2)inhibiting mechanism.Hence,in this study,reactive oxygen species(ROS)-responsive composite nano-hydrangeas loaded with the Chinese medicine small molecule allicin and platinum(IV)prodrug(DTP@AP NPs)were prepared to achieve comprehensive chemosensitization.On one front,allicin achieved COX-2 blocking therapy,en-compassing the inhibition of proliferation,angiogenesis and endothelial mesenchymal transition(EMT),thereby mitigating the adverse impacts of CDDP chemotherapy.Simultaneously,synergistic chemosensi-tization was achieved from multifaceted mechanisms by decreasing CDDP inactivation,damaging mito-chondria and inhibiting DNA repair.In essence,these findings provided an optimized approach for syner-gizing CDDP with COX-2 inhibitors,offering a promising avenue for enhancing OC treatment outcomes.

Outcome and risk factors of ulcer healing after gastric endoscopic submucosal dissection: A systematic review and meta-analysis

BACKGROUND Endoscopic submucosal dissection(ESD)is widely utilized for the treatment of large adenomas,submucosal lesions,and early gastric cancer.A significant arti-ficial ulcer typically forms after ESD.Delayed or incomplete healing of these ulcers can result in complications such as delayed bleeding and perforation.However,a comprehensive review of the outcomes and risk factors related to ulcer healing following ESD is currently lacking.AIM To assess ulcer healing outcomes and identify risk factors associated with delayed ulcer healing.RESULTS Our analysis included 12 studies,involving a total of 3430 patients.The meta-analysis revealed an overall healing rate of 65.55%for ulcers following ESD[odds ratio(OR)=2.71;95%confidence interval(CI):2.45-3.00].The healing rate within eight weeks was 48.32%(OR=0.76;95%CI:0.35-1.66),while the rate beyond eight weeks was 88.32%(OR=6.73;95%CI:3.82-11.87).Risk factors included Helicobacter pylori(H.pylori)infection(OR:=5.32;95%CI:1.90-14.87;P=0.001),ulcer size(OR=2.08;95%CI:1.19-3.61;P=0.01),lesion site(OR=2.08;95%CI:1.19-3.11),and pathological type(OR=1.64;95%CI:1.06-2.52).Diabetes(OR=0.56;95%CI:0.05-5.80;P=0.63)and duration of operation(OR=1.00;95%CI:0.99-1.01;P=0.96)were not significant factors.CONCLUSION The healing rate of ulcers following ESD is high after eight weeks.Risk factors affecting the healing process include H.pylori infection,ulcer size,lesion site,and pathological type.

Zwitterionic polymers-armored amyloid-like protein surface combats thrombosis and biofouling

Proteins,cells and bacteria adhering to the surface of medical devices can lead to thrombosis and infection,resulting in significant clinical mortality.Here,we report a zwitterionic polymers-armored amyloid-like protein surface engineering strategy we called as“armored-tank”strategy for dual functionalization of medical devices.The“armored-tank”strategy is realized by decoration of partially conformational transformed LZM(PCTL)assembly through oxidant-mediated process,followed by armoring with super-hydrophilic poly-2-methacryloyloxyethyl phosphorylcholine(pMPC).The outer armor of the“armored-tank”shows potent and durable zone defense against fibrinogen,platelet and bacteria adhesion,leading to long-term antithrombogenic properties over 14 days in vivo without anticoagulation.Additionally,the“fired”PCTL from“armored-tank”actively and effectively kills both Gram-positive and Gram-negative bacterial over 30 days as a supplement to the lacking bactericidal functions of passive outer armor.Overall,this“armored-tank”surface engineering strategy serves as a promising solution for preventing biofouling and thrombotic occlusion of medical devices.

A cigarette filter-derived biomimetic cardiac niche for myocardial infarction repair

Cell implantation offers an appealing avenue for heart repair after myocardial infarction(MI).Nevertheless,the implanted cells are subjected to the aberrant myocardial niche,which inhibits cell survival and maturation,posing significant challenges to the ultimate therapeutic outcome.The functional cardiac patches(CPs)have been proved to construct an elastic conductive,antioxidative,and angiogenic microenvironment for rectifying the aberrant microenvironment of the infarcted myocardium.More importantly,inducing implanted cardiomyocytes(CMs)adapted to the anisotropic arrangement of myocardial tissue by bioengineered structural cues within CPs are more conducive to MI repair.Herein,a functional Cig/(TA-Cu)CP served as biomimetic cardiac niche was fabricated based on structural anisotropic cigarette filter by modifying with tannic acid(TA)-chelated Cu2+(TA-Cu complex)via a green method.This CP possessed microstructural anisotropy,electrical conductivity and mechanical properties similar to natural myocardium,which could promote elongation,orientation,maturation,and functionalization of CMs.Besides,the Cig/(TA-Cu)CP could efficiently scavenge reactive oxygen species,reduce CM apoptosis,ultimately facilitating myocardial electrical integration,promoting vascular regeneration and improving cardiac function.Together,our study introduces a functional CP that integrates multimodal cues to create a biomimetic cardiac niche and provides an effective strategy for cardiac repair.

Monascus pigment-protected bone marrow-derived stem cells for heart failure treatment

Mesenchymal stem cells(MSCs)have demonstrated significant therapeutic potential in heart failure(HF)treatment.However,their clinical application is impeded by low retention rate and low cellular activity of MSCs caused by high inflammatory and reactive oxygen species(ROS)microenvironment.In this study,monascus pigment(MP)nanoparticle(PPM)was proposed for improving adverse microenvironment and assisting in transplantation of bone marrow-derived MSCs(BMSCs).Meanwhile,in order to load PPM and reduce the mechanical damage of BMSCs,injectable hydrogels based on Schiff base cross-linking were prepared.The PPM displays ROS-scavenging and macrophage phenotype-regulating capabilities,significantly enhancing BMSCs survival and activity in HF microenvironment.This hydrogel demonstrates superior biocompatibility,injectability,and tissue adhesion.With the synergistic effects of injectable,adhesive hydrogel and the microenvironment-modulating properties of MP,cardiac function was effectively improved in the pericardial sac of rats.Our results offer insights into advancing BMSCs-based HF therapies and their clinical applications.

Dynamic compliance penis enlargement patch

Men are particularly sensitive to penis size,especially those with a deformed or injured penis.This can lead to a strong desire for penis enlargement surgery.Given the ethical sensitivities of the penis,penile implants need to be developed with both efficacy and safety.In this study,a polyvinyl alcohol(PVA)patch for penile enlargement prepared via cyclic freeze‒thaw cycles and alkaline treatment.The PVA hydrogels treated with 5 M NaOH had the best mechanical properties and stability.A negative Poisson’s ratio structure is incorporated into the design of the enlargement patch,which allows it to conform well to the deformation of the penis.In rabbit models,the enlarged patches can effectively enlarge the penis without degradation or fibrosis while maintaining long-term stability in vivo.This innovation not only provides a safe option for patients in need of penile enlargement but also promises to make a broader contribution to the field of dynamic tissue repair.

An insect sclerotization-inspired antifouling armor on biomedical devices combats thrombosis and embedding

Thrombus formation and tissue embedding significantly impair the clinical efficacy and retrievability of temporary interventional medical devices.Herein,we report an insect sclerotization-inspired antifouling armor for tailoring temporary interventional devices with durable resistance to protein adsorption and the following protein-mediated complications.By mimicking the phenol-polyamine chemistry assisted by phenol oxidases during sclerotization,we develop a facile one-step method to crosslink bovine serum albumin(BSA)with oxidized hydrocaffeic acid(HCA),resulting in a stable and universal BSA@HCA armor.Furthermore,the surface of the BSA@HCA armor,enriched with carboxyl groups,supports the secondary grafting of polyethylene glycol(PEG),further enhancing both its antifouling performance and durability.The synergy of robustly immobilized BSA and covalently grafted PEG provide potent resistance to the adhesion of proteins,platelets,and vascular cells in vitro.In ex vivo blood circulation experiment,the armored surface reduces thrombus formation by 95%.Moreover,the antifouling armor retained over 60%of its fouling resistance after 28 days of immersion in PBS.Overall,our armor engineering strategy presents a promising solution for enhancing the antifouling properties and clinical performance of temporary interventional medical devices.

EGFR-mutant non-small cell lung cancer patients harboring CDK4 amplification show favorable response to afatinib:Two case reports

To the Editor:Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)show significant efficacy in patients with advanced-stage non-small cell lung cancer(NSCLC)with sensitive EGFR mutations and significantly prolong the survival of these patients.However,drug resistance emerges in most patients.Previous studies indicated that cyclin-dependent kinase 4/6(CDK4/6)gene amplification was one of the resistance mechanisms of the EGFR-TKI osimertinib,weakening its efficacy.Treatment options for EGFR-mutant NSCLC patients with CDK4 amplification are limited to add CDK4 inhibitors.

Diffusion-induced phase separation 3D printed scaffolds for dynamic tissue repair

Many hydrogen-bonded cross-linked hydrogels possess unique properties,but their limited processability hinders their potential applications.By incorporating a hydrogen bond dissociator(HBD)into these hydrogels,we developed injectable 3D printing inks termed diffusion-induced phase separation(DIPS)3D printing inks.Upon extrusion into water and subsequent diffusion of HBD,these ink cure rapidly.The DIPS-printed scaffold retained most of the original hydrogel properties due to the regeneration of hydrogen bonds.Additionally,the reversible nature of hydrogen bonds provides DIPS 3D-printed scaffolds with exceptional recycling and reprinting capabilities,resulting in a reduction in the waste of valuable raw ink materials or additives.Postprocessing introduces new crosslinking methods that modulate the mechanical properties and degradation characteristics of DIPS scaffolds over a broad range.Based on its suitable mechanical properties and bioactivity,we successfully repaired and functionally reconstructed a complex defect in penile erectile tissue using the DIPS scaffold in a rabbit model.In summary,this approach is relevant for various hydrogen-bonded cross-linked hydrogels that offer mild printing conditions and enable the incorporation of bioactive agents.They can be used as scaffolds for dynamic tissue reconstruction,wearable devices,or soft robots.

Mimicking Mytilus edulis foot protein:A versatile strategy for robust biomedical coatings

Universal coatings with versatile surface adhesion,good mechanochemical robustness,and the capacity for secondary modification are of great scientific interest.However,incorporating these advantages into a system is still a great challenge.Here,we report a series of catechol-decorated polyallylamines(CPAs),denoted as pseudo-Mytilus edulis foot protein 5(pseudoMefp-5),that mimic not only the catechol and amine groups but also the backbone of Mefp-5.CPAs can fabricate highly adhesive,robust,multifunctional polyCPA(PCPA)coatings based on synergetic catechol-polyamine chemistry as universal building blocks.Due to the interpenetrating entangled network architectures,these coatings exhibit high chemical robustness against harsh conditions(HCl,pH 1;NaOH,pH 14;H2O2,30%),good mechanical robustness,and wear resistance.In addition,PCPA coatings provide abundant grafting sites,enabling the fabrication of various functional surfaces through secondary modification.Furthermore,the versatility,multifaceted robustness,and scalability of PCPA coatings indicate their great potential for surface engineering,especially for withstanding harsh conditions in multipurpose biomedical applications.

Paired related homeobox 1 transactivates dopamine D2 receptor to maintain propagation and tumorigenicity of glioma-initiating cells

GUoblastoma multiforme （GBM） is a highly invasive brain tumor with limited therapeutic means and poor prognosis. Recent stud- ies indicate that glioma-initiating ceUs/gUoma stem ceils （GICs/GSCs） may be responsible for tumor initiation, infiltration, and recurrence. GICs could aberrantly employ molecular machinery balancing self-renewal and differentiation of embryonic neural precursors. Here, we find that paired related homeobox 1 （PRRX1）, a homeodomain transcription factor that was previously reported to control skeletal development, is expressed in cortical neural progenitors and is required for their self-renewal and proper differentiation. Further, PRRX1 is overrepresented in gUoma samples and labels GlCs. Gtioma celts and GlCs depleted with PRRX1 could not propagate in vitro or form tumors in the xenograft mouse model. The GIC self-renewal function regulated by PRRX1 is mediated by dopamine D2 receptor （DRD2）. PRRX1 directly binds to the DRD2 promoter and transactivates its expression in GICs. Blockage of the DRD2 signaling hampers GIC self-renewal, whereas its overexpression restores the propagating and tumorigenic potential of PRRXl-depleted GlCs. Finally, PRRX1 potentiates GICs via DRD2-mediated extracetlutar signal-related kinase （ERK） and AKT activation. Thus, our study suggests that therapeutic targeting the PRRX1-DRD2-ERK/AKT axis in GICs is a promising strategy for treating GBMs.