Gliomas are highly malignant brain tumors characterized by an immunosuppressive microenvironment, which limits therapeutic efficacy and contributes to poor clinical outcomes. The WNT/β-catenin signaling pathway is critically involved in tumor progression, and FZD5, a key receptor within this pathway, may participate in immune regulation. However, its specific role and underlying mechanisms in glioma remain unclear. RNA-seq and microarray datasets from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA), together with single-cell RNA sequencing (scRNA-seq) datasets from GEO, were comprehensively analyzed. The Seurat package was used to identify macrophage-related clusters and mitophagy-associated pathways. Cox and LASSO regression analyses, along with a prognostic nomogram, were applied to evaluate the prognostic significance of FZD5. Immune infiltration, functional enrichment, and immunotherapy response analyses were conducted, followed by validation using spatial transcriptomics, immunohistochemistry, and in vitro assays. In bulk glioma transcriptomes, FZD5 emerged as an independent predictor of poor prognosis. Crucially, single-cell and spatial analyses revealed that the biologically significant FZD5 signal originated predominantly within tumor-associated macrophages (TAMs), where it colocalized with the M2 marker CD163. Consistently, elevated FZD5 levels correlated with increased myeloid infiltration and an immunosuppressive tumor microenvironment. Functionally, macrophage-expressed FZD5 was associated with mitophagy-related programs and promoted an M2-skewed phenotype, thereby enhancing glioma cell proliferation, migration, and invasion via macrophage–glioma crosstalk. FZD5 is a TAM-enriched marker in glioma tissues and a potential regulator of macrophage-associated immunosuppressive programs, supporting its utility as a prognostic biomarker and a candidate target for microenvironment-oriented interventions in glioma.

Due to complex immune and metabolic dysfunctions, diabetic wounds commonly suffer from infection, oxidative stress, impaired angiogenesis, thereby leading to chronic non-healing lesions. Since current therapies remain insufficient, increasing attention has been directed toward mitophagy, a key regulator of energy balance and stress responses, with mitochondrial dysfunction recognized as a critical driver of defective repair. In this study, we explored the therapeutic role of echinacoside (Ech), a phenylethanol glycoside from Echinacea, known for its potent antioxidant, anti-inflammatory, and pro-angiogenic properties, in promoting diabetic wound healing. Network pharmacology analysis was employed to identify the potential targets of Ech in diabetic condition. In vitro, under H2O2-induced oxidative stress, Ech mitigated the functional impairment of human umbilical vein endothelial cells (HUVECs), enhancing their proliferation, migration, angiogenesis, and antioxidant capacity. Mechanistically, Ech restored HUVECs function by activating Parkin-MFN2-mediated mitophagy through ubiquitination and concurrently upregulated USP35 expression, which mitigated excessive mitophagy. These effects were confirmed using the Parkin-dependent mitophagy inhibitor cyclosporin A (CsA) and USP35-specific siRNA (siUSP35). In a diabetic mouse full-thickness cutaneous wound model, Ech treatment significantly activated Parkin-dependent mitophagy, leading to enhanced neovascularization and collagen deposition at wound site, thereby accelerated the healing process of diabetic wounds. Collectively, these findings identify Ech as a promising therapeutic agent for diabetic wound repair and provide mechanistic insights into its regulation of mitophagy to improve antioxidant responses and angiogenesis, offering a foundation for the development of targeted treatment strategies.

BACKGROUND:Psoriasis is a chronic immune-mediated skin condition characterized by excessive epidermal growth and persistent inflammation. Although current therapies improve disease outcomes, limitations in long-term efficacy and safety remain. Fibroblast growth factor 21 (FGF21), involved in metabolic regulation, has been reported to display anti-inflammatory activity and support tissue homeostasis; however, its role in psoriasis is not fully understood. METHODS:A psoriasis-like mouse model established by imiquimod (IMQ) application was used to assess the in vivo activity of FGF21. Histopathological examination, cytokine analysis, immunohistochemistry, and western blotting were conducted to assess epidermal alterations and signaling pathways. In vitro, lipopolysaccharide-stimulated HaCaT keratinocytes were used to examine the impact of FGF21 on cell proliferation, apoptosis, and inflammatory mediator expression, while primary normal human epidermal keratinocytes (NHEKs) were incorporated for validation. Furthermore, pathway alterations were evaluated, and pharmacological inhibition with chloroquine (CQ) was used to assess autophagy dependence. RESULTS:FGF21 administration attenuated psoriasis-like skin lesions, reduced systemic inflammatory cytokine levels in IMQ-treated mice, and exhibited preliminary tolerability based on body weight and histology. In keratinocytes, FGF21 partially restored proliferation-apoptosis balance and suppressed inflammation, associated with reduced NF-κB activation. FGF21 also modulated autophagy-related proteins alongside PI3K/AKT inhibition, with increased SIRT1 expression and decreased STAT3 activation. Crucially, CQ perturbation revealed that the anti-inflammatory and anti-proliferative benefits of FGF21 depended on autophagy restoration. CONCLUSIONS:FGF21 modulates key inflammatory and autophagy-related signaling pathways in psoriasis-like mice model and may represent a promising therapeutic candidate in psoriasis and other autoimmune inflammatory disorders.

Microtubule-targeting agents constitute a cornerstone of cancer chemotherapy, yet drug resistance remains a major challenge. Signal transducer and activator of transcription-3 (STAT3) inhibition may potentiate chemosensitivity and circumvent resistance mechanisms. During a phenotypic screen of anticancer agents, a small-molecule compound IMB5023 emerged as a promising candidate. In the present work, we report its antitumor efficacy and mechanism of action. IMB5023 exhibited cytotoxicity across multiple cancer cell lines, inducing pyroptosis in gasdermin E-positive cells and apoptosis in gasdermin E-negative cells. Transcriptomic profiling revealed that IMB5023 targeted centrosome-related pathway and impaired mitotic spindle assembly. Immunofluorescence analysis revealed concentration-dependent effects: multipolar spindle formation at a low concentration (1 μM) and microtubule network disruption at a higher concentration (10 μM). Furthermore, IMB5023 suppressed STAT3 pathway in vitro and overcame multidrug resistance by downregulating drug efflux pump ATP-binding cassette sub-family G member 2 (ABCG2) and anti-apoptotic protein B-cell lymphoma-extra large (Bcl-XL). Notably, IMB5023 triggered immunogenic cell death and enhanced dendritic cell phagocytosis. In vivo, IMB5023 inhibited tumor growth by 52%. Tumor histopathology confirmed centrosome declustering and STAT3 pathway inhibition. Collectively, IMB5023 concurrently disrupts microtubules and inhibits STAT3 pathway. This dual mechanisms of action positions IMB5023 as a promising therapeutic candidate, particularly for resistant malignancies.

PURPOSE:Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and fatal malignancy, although gemcitabine is administered as a single or combined therapeutic agent. Our previous study demonstrated that ANP32E overexpression promoted PDAC cell proliferation. However, whether it affects treatment outcome and clinical prognosis is still unclear. In the present study, we aimed to determine whether ANP32E is negatively associated with the treatment outcome of gemcitabine. METHODS:We collected clinical characteristics and treatment information from a total of 75 PDAC patients to assess the association of ANP32E expression via immunohistochemical (IHC) staining with overall survival (OS) in patients who were or were not treated with gemcitabine-based chemotherapy, followed by a clinical replication study with transcriptomic data from the TCGA database and functional validation experiments involving the knockdown of ANP32E in the Hup-T3 and SU86.86 human pancreatic cancer cell lines. RESULTS:We demonstrated the interference effect of ANP32E on gemcitabine efficacy and patient prognosis in PDAC patients by using our own clinical samples or publicly available TCGA datasets. Downregulation of ANP32E significantly sensitized Hup-T3 and SU86.86 cells to gemcitabine, which was consistent with the results of the above association studies. CONCLUSION:Our findings suggest that ANP32E might serve as a negative biomarker for poor prognosis and a predictive indicator for poor gemcitabine efficacy. These findings suggest that ANP32E might be a potential therapeutic target to help develop effective drugs to overcome gemcitabine resistance and reduce the risk for relapse or metastasis in patients with PDAC.

Diabetic wound healing remains a significant challenge, due to chronic inflammatory apoptotic cells accumulation. Herein, an immuno-bioenergy regulated hydrogel (CCE) is reported, which converts apoptotic cells into cytokines that facilitate tissue repair. The CCE consisted of a poly(citrate-curcumin) and erastin cross-linked thermosensitive network, which enhanced efferocytosis in dendritic cells (DCs) by the sustained release of erastin and reinforced the cellular energy metabolism by intracellular release of citrate. With the promoted efferocytosis and increased secretion of anti-inflammatory and pro-reparative cytokines, macrophages are effectively polarized towards M2 phenotype via activation of JAK1/STAT3 pathway, while the damaged function of fibroblasts and endothelial cells under high-glucose conditions is restored. Moreover, the released citrate increased intracellular citrate level, modulating the high glucose-induced energy metabolites disturbances and alleviating mitochondrial dysfunction in endothelial cells. Notably, this combination exhibited a synergistic effect in promoting endothelial cells angiogenesis and immunoregulation ability of macrophages. In a diabetic wound model, CCE hydrogel facilitated the diabetic wounds repair, characterized by a reduced inflammation, enhanced angiogenesis and collagen deposition. These outcomes are attributed to immune microenvironment reconstruction through enhanced efferocytosis-mediated clearance of apoptotic cells and M2 polarization of macrophages. This work presents a novel strategy that leverages efferocytosis and the immune microenvironment modulation to facilitate diabetic wounds healing.

Uncontrolled bleeding post-surgery or trauma presents a significant medical challenge that often leads to complications such as hypotension, organ dysfunction, and mortality. Effective hemostatic agents are characterized by facilitating rapid bleeding cessation, adequate wet tissue adhesion, easy removal, and minimal hemolysis rate. Building on our previous work with tsPBA@PVA hydrogel, we developed a modified synthesis approach to yield Fe3O4@gel, designed to enhance hemostasis. This system is composed of Fe3O4, N1-(4-boronobenzyl)-N3-(4-boronophenyl)-N1,N1,N3,N3-tetramethylpropane-1,3-diaminium, tsPBA, and polyvinyl alcohol, PVA, which undergo a reaction to yield a borate ester. The hydrogel demonstrated excellent self-healing and adhesion properties by forming covalent bonds with diols on material surfaces. Moreover, the presence of polar functional groups within the hydrogel such as -OH, -CH, and -CO groups enabled strong hydrogen bonding with tissue surfaces. The hydrogel could also be easily removed from the wound site without causing rebleeding. In vitro, Fe3O4@gel exhibited a hemolysis rate of less than 5%. Both our in vivo and in vitro results demonstrated the formation of a blood clot enhanced by the presence of Fe3O4 in the hydrogel. These findings suggest the potential of Fe3O4@gel as a promising candidate for promoting hemostasis in wound healing.

Pharmaceutical graduate education often faces a gap between basic theoretical knowledge and the practical realities of drug research, resulting in a limited understanding of new drug development among graduate students. Therefore, it is necessary to implement pharmaceutical education based on the principles and practices of translational medicine to help students gain a deeper understanding of the drug development process and to cultivate professionals capable of translating basic research findings into clinical applications. Pharmaceutical graduate students at Campus A (172 students) were taught using traditional methods, while students at Campus B (203 students) were taught using a reformed approach. The reformed class focused on building an interdisciplinary teaching team, selecting faculty with experience in new drug development and a background in translational medicine, to strengthen the connection between clinical and basic research. Additionally, the course content was designed to reflect the latest advancements in the field, breaking away from traditional textbooks. Various disease models were used to explain the application of translational medicine in pharmacy. The course employed a variety of teaching methods, including theoretical lectures, interactive seminars, case discussions, and expert-led workshops, to enhance students’ understanding of cutting-edge topics and stimulate innovative thinking while addressing real-world clinical issues. Finally, the assessment focused on process-oriented evaluation, using group presentations, literature reviews, and other diverse methods to comprehensively assess both academic and practical abilities. The comparison of theoretical knowledge exam scores (converted to a percentage scale) between the traditional and reformed class revealed a statistically significant difference (P < 0.05), indicating that students in the reformed class had a better grasp of the theoretical knowledge. In the innovative drug development proposal project, the traditional class consisted of 17 teams, while the reformed class had 20 teams. The independent t-test showed a significant difference in the average scores between the two groups (P < 0.01), suggesting that the reformed class developed stronger drug development strategies based on clinical problems. Furthermore, the results of the student satisfaction survey indicated that students in the reformed class responded positively to the new teaching methods, with only a single-digit number of students reporting dissatisfaction, indicating broad acceptance. The reform of the pharmaceutical graduate course “Biopharmaceuticals and Translational Medicine,” based on the principles of translational medicine, not only enhances students’ understanding of the drug development process but also better prepares them for careers in pharmaceutical research and clinical applications.

Melanoma presents as an increasingly prevalent and intricate skin cancer, characterized by a complex tumor microenvironment that features various mutations and the activation of melanogenesis pathways. Dynamic changes within this microenvironment, including increased ROS levels, acidity, and enzyme expression, specifically upregulation of glutaryl-CoA dehydrogenase and MMP2, amongst other enzymes, further contribute to its complexity. Despite advancements in melanoma treatment and FDA approval of therapies targeting specific pathways and employing immune checkpoint inhibitors, challenges persist in melanoma treatment, particularly in optimizing drug delivery and navigating the intricate tumor microenvironment. Recent research has increasingly focused on integrating biomaterials into melanoma treatment, yielding promising results. These biomaterials find application in melanoma diagnosis, treatment, and imaging. Studies have sparked interest in uncovering the therapeutic potential of stimuli-responsive biomaterials. pH-responsive systems offer the prospect of targeted drug release in the acidic tumor microenvironment. Meanwhile, light- and temperature-responsive materials offer spatiotemporal control, aiding melanoma death processes such as necroptosis, apoptosis, and necrosis. Biomaterials responsive to ROS and enzymes address the intricacies of melanoma biology, enhancing treatment specificity. Additionally, multiple stimuli-responsive platforms present a holistic approach for heightened therapeutic efficacy. This review navigates the intricate terrain of melanoma treatment, addressing current therapy limitations and envisioning a future where functionalized biomaterials are pivotal in more effective and targeted interventions. We evaluate multifaceted approaches harnessing distinct biological, physical, and chemical stimuli, and their synergistic combinations to enhance drug delivery precision and other mechanisms in melanoma.

As a radiomimetic antitumor antibiotic, lidamycin (LDM) contains an enediyne chromophore and an apoprotein LDP. Potent cytotoxicity and lack of tumor localization limited its clinical application. Though a series of fusion proteins composed of LDM and tumor-targeting moieties has been prepared and ameliorated LDM's antitumor activity, the complicated preparation process and the low reconstitution efficacy of chromophore limited their developments. Here, we report an albumin-binding LDM prodrug for efficient targeted cancer chemotherapy. LDM or rLDP (recombinant LDP) was modified with Sulfo-SMCC to produce Mal-LDM and Mal-rLDP by a one-step reaction. LC-MS assay demonstrated that one maleimide group was successfully conjugated to rLDP. Mal-rLDP bound to albumin quickly in vitro and in vivo. After intravenous injection, Cy7-labelled Mal-rLDP mainly localized at the tumor site and displayed extended serum half-life. Mal-LDM showed similar cytotoxicity compared with LDM in vitro. In vivo, Mal-LDM showed increased antitumor activity and decreased cytotoxicity compared with LDM. All of those results demonstrate that Mal-LDM is a promising prodrug which could be used in clinic after a simple modification of LDM.

Purpose Endosome associated trafficking regulator 1 (ENTR1) is a novel endosomal protein, which can affect multiple cellular biological behavior by remodeling plasma membrane structures. However, little is known regarding its function and underlying mechanisms in glioblastoma multiforme. Methods Expression profile and clinical signature were obtained from The Public Database of human tumor. Immunohistochemical staining and western blotting assays were used to measure ENTR1 expression level. Human primary GBM tumor cells and human GBM cell lines A172, U87 and U251 were used to clarify the precise role of ENTR1. CCK-8 assays, wound healing and transwell invasion assays were designed to investigate cell viability, invasion and migration of GBM cells, respectively. Underlying molecular mechanisms of ENTR1 were determined via RNA-seq analysis. Tumor formation assay was used to validate the influence of ENTR1 in vivo. Results Compared with normal brain tissues, ENTR1 was highly expressed in gliomas and correlated with malignant grades of gliomas and poor overall survival time. The proliferation and invasion of GBM cells could be weaken and the sensitivity to temozolomide (TMZ) chemotherapy increased after knocking down ENTR1. Overexpression of ENTR1 could reverse this effect. RNA-seq analysis showed that tumor necrosis factor (TNF) signaling pathway might be a putative regulatory target of ENTR1. Tumor formation assay validated that ENTR1 was a significant factor in tumor growth. Conclusion Our results indicated that ENTR1 played an important role in cell proliferation, invasion and chemotherapeutic sensitivity of GBM, suggesting that ENTR1 might be a novel prognostic marker and significant therapeutic target for GBM.

Pancreatic ductal adenocarcinoma (PDAC) patients have an unfavorable prognosis and disappointing treatment outcomes because of late diagnosis, high chemotherapy resistance, ineffective adjuvant chemotherapy, unavailable molecular targeted therapy, and profound immunosuppressive effects in the tumor microenvironment (TME). There are a variety of critical driver proteins, such as KRAS, TP53, PTEN and SMAD4, putatively involved in PDAC etiology. Current knowledge of their molecular mechanisms is still limited. SMAD4 gene alterations in ∼55 % of patients emphasize its key role in PDAC progression, metastasis, resistance and immunity. Despite extensive studies on the TGF-β/SMAD pathway, the impact of SMAD4 mutation/deficiency on PDAC prognosis and treatment, especially its mechanism in drug resistance, has not yet been elucidated. This review summarizes the latest advances in the effect of SMAD4 deficiency on the prognosis and therapeutic resistance of PDAC patients. It might be a predictive and prognostic biomarker or therapeutic target to achieve the desired clinical benefits. Moreover, we discuss potential strategies to implement targeted therapies in terms of SMAD4 genetic status.

Background: Hepatocellular carcinoma (HCC) is a common disease in human history and one of the main causes of cancer-related death. Insufficient oxygen supply in the tumor microenvironment forces cancer cells to survive in a mild hypoxia environment. Fibroblast growth factor 21 (FGF21), a member of the FGF family, has become the focus of public attention due to its outstanding achievements in diabetes and lipid lowering. However, the mechanism of FGF21 in HCC remains unclear. Objective: The aims of this study were to clarify whether or not FGF21 could increase the sensitivity of sorafenib (SORA) to HCC under hypoxia and explore the possible mechanism. Methods: In this study, by using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide cell viability test, plate clone formation test, western blot analysis, Hoechst/propidium iodide double staining experiment, flow cytometry, quantitative reverse transcription polymerase chain reaction, and subcutaneous tumor transplantation in mice, we studied the effects of recombinant human FGF21 combined with SORA on hepatoma cells in vitro and in vivo. FGF21 could enhance the phosphorylation of mothers against decapentaplegic homolog 3 (Smad3) under anaerobic conditions. When combined with SORA, FGF21 could increase the sensitivity of hepatoma cells to SORA and inhibit the growth and migration of hepatoma cells. Results: FGF21 may increase the sensitivity of HCC to SORA by enhancing the phosphorylation of Smad3 through the phosphatidylinositol 3-kinase/protein kinase B pathway under hypoxia. Conclusion: Our study suggested the possibility of combination therapy for SORA and FGF21 on HCC.

Due to their simplicity and reliability, random-pattern skin flaps are commonly utilized in surgical reconstruction to repair cutaneous wounds. However, the post-operative necrosis frequently happens because of the ischemia and high-level of oxidative stress of random skin flaps, which can severely affect the healing outcomes. Earlier evidence has shown promising effect of Nuciferine (NF) on preventing hydrogen peroxide (H2O2)-induced fibroblast senescence and ischemic injury, however, whether it can function on promoting ischemic flap survival remains unknown. In this work, using network pharmacology analysis, it was possible to anticipate the prospective targets of NF in the context of ischemia. The results revealed that NF treatment minimized H2O2-induced cellular dysfunction of human umbilical vein endothelial cells (HUVECs), and also improved flap survival through strengthening angiogenesis and alleviating oxidative stress, inflammation and apoptosis in vivo. These outcomes should be attributed to TFEB-mediated enhancement of autophagy-lysosomal degradation via the AMPK-mTOR signaling pathway, whilst the restriction of autophagy stimulation with 3MA effectively diminished the above advantages of NF treatment. The increased nuclear translocation of TFEB not only restored lysosome function, but also promoted autophagosome-lysosome fusion, eventually restoring the inhibited autophagic flux and filling the high energy levels. The outcomes of our research can provide potent proof for the application of NF in the therapy of vascular insufficiency associated disorders, including random flaps.

Achieving rapid healing of chronic wounds is still highly demanded. In the last few decades, exogenous administration of basic fibroblast growth factor (bFGF) in both clinical and preclinical investigations has proven to be therapeutically effective. However, the adverse wound environment (e.g., increased inflammation) de-teriorates the functionality of bFGF. Therefore, improvements of the wound "soil" in addition to the use of bFGF is of importance to future clinical success. To address this issue, we designed an injectable host-guest drug delivery system for the controlled release of the hydrophilic bFGF alongside the hydrophobic anti-inflammatory drug, Pinocembrin (PNCB), to promote effective wound repair. The hydrophobic PNCB was first loaded into Pluronic F127 micelles (PNCB@F127) and then threaded onto bFGF-mixed alpha-cyclodextrin (alpha-CD) chains to form the host-guest hydrogel (P/bFGF@F127 alpha-CD). The in vitro and in vivo results demonstrated that P/bFGF@F127 alpha-CD could effectively accelerate wound healing by combining the therapeutic effects of both PNCB and bFGF. The results showed the potential of combining anti-inflammatory drugs with growth factors for wound healing.

Background Pyroptosis, a lytic form of programmed cell death initiated by inflammasomes, has been reported to be closely associated with tumor proliferation, invasion and metastasis. However, the roles of pyroptosis genes (PGs) in low-grade glioma (LGG) remain unclear. Methods We obtained information for 1,681 samples, including the mRNA expression profiles of LGGs and normal brain tissues and the relevant corresponding clinical information from two public datasets, TCGA and GTEx, and identified 45 differentially expressed pyroptosis genes (DEPGs). Among these DEPGs, nine hub pyroptosis genes (HPGs) were identified and used to construct a genetic risk scoring model. A total of 476 patients, selected as the training group, were divided into low-risk and high-risk groups according to the risk score. The area under the curve (AUC) values of the receiver operating characteristic (ROC) curves verified the accuracy of the model, and a nomogram combining the risk score and clinicopathological characteristics was used to predict the overall survival (OS) of LGG patients. In addition, a cohort from the Gene Expression Omnibus (GEO) database was selected as a validation group to verify the stability of the model. qRT-PCR was used to analyze the gene expression levels of nine HPGs in paracancerous and tumor tissues from 10 LGG patients. Results Survival analysis showed that, compared with patients in the low-risk group, patients in the high-risk group had a poorer prognosis. A risk score model combining PG expression levels with clinical features was considered an independent risk factor. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that immune-related genes were enriched among the DEPGs and that immune activity was increased in the high-risk group. Conclusion In summary, we successfully constructed a model to predict the prognosis of LGG patients, which will help to promote individualized treatment and provide potential new targets for immunotherapy.

ACT001, derived from traditional herbal medicine, is a novel compound with effective anticancer activity in clinical trials. However, little is known regarding its role in pituitary adenomas. Here, we demonstrated that ACT001 suppressed cell proliferation and induced cell death of pituitary tumor cells in vitro and in vivo. ACT001 was also effective in suppressing the growth of different subtypes of human pituitary adenomas. The cytotoxic mechanism ACT001 employed was mainly related to autophagic cell death (ACD), indicated by autophagosome formation and LC3-II accumulation. In addition, ACT001-mediated inhibitory effect decreased when either ATG7 was downregulated or cells were cotreated with autophagy inhibitor 3-methyladenine (3-MA). RNA-seq analysis showed that mitogen-activated protein kinase (MAPK) pathway was a putative target of ACT001. Specifically, ACT001 treatment promoted the phosphorylation of JNK and P38 by binding to mitogen-activated protein kinase kinase 4 (MEK4). Our study indicated that ACT001-induced ACD of pituitary tumor cells via activating JNK and P38 phosphorylation by binding with MEK4, and it might be a novel and effective anticancer drug for pituitary adenomas.

Serum orosomucoid1-like protein 3 (ORMDL3) is a membrane protein in the endoplasmic reticulum, known to regulate many important signal transduction processes and autophagy regulation, but it is unclear whether it is involved in the intratumoral microenvironment and cancer drug resistance. Our present study found that silencing ORMDL3 increases the inhibitory effect of sorafenib on the viability and proliferation in HCC cells, and increases the sensitivity of HCC cells to sorafenib. In addition, silencing ORMDL3 can increase ROS levels by inhibiting autophagy, thereby increasing sorafenib-induced apoptosis of HCC cells. Further, our study also found that ORMDL3 silencing inhibits autophagy through the PERK-ATF4-Beclin1 pathway, thus affecting sorafenib sensitivity. The in vivo effects of sorafenib were tested by xenografting using nude mice. It showed that silencing ORMDL3 in HCC cells could increase the inhibitory effect of sorafenib on the growth of tumors. This is the first report to describe the relationships among ORMDL3, autophagy, and sorafenib resistance. This study provides available targets that might have a synergetic effect with sorafenib.

[This corrects the article DOI: 10.7150/thno.29766.].

Brusatol (Bru), a Chinese herbal extract, has a variety of anti-tumor effects. However, little is known regarding its role and underlying mechanism in glioblastoma cells. Here, we found that Bru could inhibit the proliferation of glioblastoma cells in vivo and in vitro. Besides, it also had an inhibitory effect on human primary glioblastoma cells. RNA-seq analysis indicated that Bru possibly achieved these effects through inhibiting the expression of extracellular matrix protein 1 (ECM1). Down-regulating the expression of ECM1 via transfecting siRNA could weaken the proliferation and invasion of glioblastoma cells and promote the inhibitory effect of Bru treatment. Lentivirus-mediated overexpression of ECM1 could effectively reverse this weakening effect. Our findings indicated that Bru could inhibit the proliferation and invasion of glioblastoma cells by suppressing the expression of ECM1, and Bru might be a novel effective anticancer drug for glioblastoma cells.