Spinal cord injury (SCI) creates a mechanically discontinuous and biochemically hostile lesion niche marked by oxidative stress, persistent inflammation, vascular dysfunction, and poor graft retention, which together limit cell-based repair. Here, we report a coordination-engineered living therapeutic interface that converts extracellular matrix (ECM)-rich human umbilical cord mesenchymal stem cell sheets (CSs) from passive grafts into microenvironment-regulating implants. A zinc metal–phenolic network (Zn MPN), formed through tannic acid/zinc ion coordination, was assembled across the sheet surface and accessible ECM domains to generate ZM-CS. This lesion-facing interface preserved sheet architecture, increased construct-level Zn incorporation, slowed degradation, and showed a qualitatively more sustained lesion-associated fluorescence signal after implantation. Under hydrogen peroxide-induced stress, ZM-CS reduced intracellular reactive oxygen species (ROS), preserved the viability of PC12 neuronal-like cells and human umbilical vein endothelial cells (HUVECs), and improved endothelial invasion and tube formation more effectively than unmodified CS. It was also associated with a repair-supportive shift in BV2 microglial inflammatory phenotype, with reduced iNOS-associated pro-inflammatory features and enhanced Arg-1-associated reparative characteristics. Transcriptomic profiling associated this cytoprotection with a repair-compatible neuronal-like cell state characterized by coordinated redox adaptation and enrichment of proliferation-, cytoskeleton-, and repair-associated programs. In a rat spinal cord hemisection model, ZM-CS improved long-term locomotor recovery, gait-related parameters, vascular remodeling, neural structural preservation, and lesion-site inflammatory regulation.

White Spot Syndrome Virus (WSSV) poses a major challenge to crustacean aquaculture, causing White Spot Disease (WSD) and significant economic losses worldwide. Despite its high infectivity, effective control strategies for WSSV are still lacking. In this study, 30 medicinal plants were screened, and C. fraxini was identified as a strong inhibitor of WSSV proliferation. Its active compound, esculetin, demonstrated potent antiviral activity, achieving 98.56 % inhibition at 80 mg/kg. Further analysis showed that esculetin inhibits WSSV replication in a dose-dependent manner, reduces viral transcription, and improves the resilience of infected crayfish. In both prophylactic and therapeutic treatments, as well as cohabitation assays, esculetin significantly decreased pathogen loads and prevented inter-host transmission, underscoring its potential as an effective disease control strategy. Esculetin works through multiple mechanisms: it suppresses viral genes involved in WSSV transcription, disrupts the virus's ability to manipulate host immune signaling, and interferes with its replication cycle. Additionally, esculetin modulates key enzymes, stabilizes apoptotic pathways, and mitigates oxidative stress and inflammation caused by infection. By restoring proteostasis and boosting host defense, esculetin ultimately enhances crayfish resistance to WSSV. These findings shed light on the pharmacological properties of esculetin and provide a strong rationale for its development as a potential agent to control WSSV outbreaks, supporting the sustainability of crustacean aquaculture.

Spinal cord injury (SCI) is a devastating central nervous system disorder that remains a global health challenge. SCI-induced oxidative stress in the postinjury microenvironment limits tissue repair by provoking the excessive production of reactive oxygen species (ROS). Tea polyphenols (TP), as a natural plant polyphenol, could effectively reduce ROS. In recent years, stem cell-based therapy combined with cell sheet technology has been widely used in the treatment of SCI. Therefore, we constructed human umbilical cord mesenchymal stem cell sheet loaded with TP (CS-TP) and evaluated their therapeutic effects and mechanisms both in vitro and in vivo in SCI rats. Human umbilical cord mesenchymal stem cell sheet (CS) were prepared by temperature-responsive cell culture method and successfully loaded with TP. The protective effect of CS and CS-TP on cells against oxidative stress was tested by Live/Dead cell staining and CCK-8 assay. CS and CS-TP were co-cultured with PC12 cells and human umbilical vein endothelial cells (HUVECs), respectively, and their effects on reducing ROS production were evaluated using flow cytometry and ROS fluorescence assays. Immune fluorescence (IF) and Western blot analysis of the mechanism by which CS-TP affects PC12 cells and HUVECs in vitro. Wound healing assay, transwell Chamber invasion experiment and tube formation assay were performed to evaluate the effects of CS and CS-TP on the biological behaviors of HUVECs. (Basso-Beattie-Bresnahan) BBB scores and gait analysis were performed to assess the recovery of motor function in rats. Molecular modeling is used to study the affinity between the main active ingredient epigallocatechin gallate (EGCG) in TP and target proteins. Western blot analyzes the mechanism of action of CS and CS-TP in SCI animals and the expression levels of antioxidant proteins. Tissue IF staining was used to evaluate angiogenesis, neuron regeneration and axonal extension. Compared with CS, CS-TP could effectively reduce cellular ROS production and increase cell viability under high oxidative stress conditions and significantly enhance its biological activity. In vitro, CS-TP can significantly activate the Keap-1/Nrf2/HO-1 pathway, thereby affecting PC12 cells and HUVECs. After transplantation in SCI rats, CS-TP also activates the Keap-1/Nrf2/HO-1 pathway, influencing the repair of SCI and upregulating the expression of SOD1 and SOD2. CS-TP can more effectively promote angiogenesis, neuronal regeneration, and axonal extension in injured spinal cords, greatly improving the motor function of the rats. CS-TP not only significantly enhances the resistance of CS to ROS, activates the Keap-1/Nrf2/HO-1 pathway, and regulates the level of antioxidant proteins in the body. Compared to CS, it can also more effectively increase the number of new blood vessels, promote neuron regeneration and axon extension, thereby more effectively repairing SCI.

BACKGROUND:In recent years, the utilization of stem cell therapy and cell sheet technology has emerged as a promising approach for addressing spinal cord injury (SCI). However, the most appropriate cell type and mechanism of action remain unclear at this time. This study sought to develop an SCI rat model and evaluate the therapeutic effects of human umbilical cord mesenchymal stem cell (hUC-MSC) sheets in this model. Furthermore, the mechanisms underlying the vascular repair effect of hUC-MSC sheets following SCI were investigated. METHODS:A temperature-responsive cell culture method was employed for the preparation of hUC-MSC sheets. The extracellular matrix (ECM) produced by hUC-MSCs serves two distinct yet interrelated purposes. Firstly, it acts as a biologically active scaffold for transplanted cells, facilitating their attachment and proliferation. Secondly, it provides mechanical support and bridges spinal cord stumps, thereby facilitating the restoration of spinal cord function. The formation of the cavity within the spinal cord was evaluated using the Hematoxylin and Eosin (H&E) staining method. Subsequently, endothelial cells were cultivated with the conditioned medium (CM) obtained from hUC-MSCs or hUC-MSC sheets. The pro-angiogenic impact of the conditioned medium of hUC-MSCs (MSC-CM) and the conditioned medium of hUC-MSC sheets (CS-CM) was evaluated through the utilization of the CCK-8 assay, endothelial wound healing assay, and tube formation assay in an in vitro context. The development of glial scars, blood vessels, neurons, and axons in hUC-MSCs and hUC-MSC sheets was assessed through immunofluorescence staining. RESULTS:In comparison to hUC-MSCs, hUC-MSC sheets demonstrated a more pronounced capacity to facilitate vascular formation and induce the regeneration of newborn neurons at the SCI site, while also reducing glial scar formation and significantly enhancing motor function in SCI rats. Notably, under identical conditions, the formation of cell sheets has been associated with a paracrine increase in the ability of the cells themselves to secrete pro-angiogenic growth factors. During the course of the experiment, it was observed that the secretion of uPAR was the most pronounced among the pro-angiogenic factors present in MSC-CM and CS-CM. This finding was subsequently corroborated in subsequent experiments, wherein uPAR was demonstrated to promote angiogenesis via the PI3K/Akt signaling pathway. CONCLUSION:The creation of cell sheets not only significantly enhances the biological function of hUC-MSCs but also effectively retains the cells locally in spinal cord injury. Therefore, the transplantation of hUC-MSC sheets can maximize the function of hUC-MSCs, greatly reducing glial scar formation, enhancing vascular formation, and promoting the regeneration of neurons and axons. Additionally, the research findings prove that hUC-MSC sheets activate the PI3K/Akt signaling pathway through uPAR secretion to enhance angiogenesis. The transfer of the entire extracellular matrix by hUC-MSC sheets, in the absence of the introduction of additional exogenous or synthetic biomaterials, serves to further augment their potential for clinical application.

BACKGROUND: Cms1 ribosomal small subunit homolog (CMSS1) is an RNA-binding protein that may play an important role in tumorigenesis and development. OBJECTIVE: RNA-seq data from the GEPIA database and the UALCAN database were used to analyze the expression of CMSS1 in liver hepatocellular carcinoma (LIHC) and its relationship with the clinicopathological features of the patients. METHODS: LinkedOmics was used to identify genes associated with CMSS1 expression and to identify miRNAs and transcription factors significantly associated with CMSS1 by GSEA. RESULTS: The expression level of CMSS1 in hepatocellular carcinoma tissues was significantly higher than that in normal tissues. In addition, the expression level of CMSS1 in advanced tumors was significantly higher than that in early tumors. The expression level of CMSS1 was higher in TP53-mutated tumors than in non-TP53-mutated tumors. CMSS1 expression levels were strongly correlated with disease-free survival (DFS) and overall survival (OS) in patients with LIHC, and high CMSS1 expression predicted poorer OS ( P < 0.01) and DFS ( P < 0.01). Meanwhile, our results suggested that CMSS1 is associated with the composition of the immune microenvironment of LIHC. CONCLUSIONS: The present study suggests that CMSS1 is a potential molecular marker for the diagnosis and prognostic of LIHC.

OBJECTIVE:Berberine (BBR) has emerged as a promising therapeutic agent for nonalcoholic fatty liver disease (NAFLD). This study aims to elucidate the underlying molecular mechanisms. METHODS:In this study, db/db mice were chosen as an animal model for NAFLD. A total of 10 healthy C57BL/6J mice and 30 db/db mice were randomly allocated to one of 4 groups: the normal control (NC) group, the diabetic control (DC) group, the Metformin (MET) therapy group, and the BBR therapy group. The total cholesterol (TC), triacylglycerol (TG), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the serum were measured. The glutathione peroxidase (GSH-Px), glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), interleukin (IL)-1β, tumor necrosis factor (TNF)-α and monocyte chemotactic protein 1 (MCP-1) levels in liver tissue were measured. Hematoxylin and eosin (H&E), acid-Schiff (PAS) and TUNEL stanning was performed for histopathological analysis. Western blotting and immunohistochemistry were conducted to detect the expression levels of key proteins in the AMPK/SIRT1 pathway. RESULTS:BBR could improve lipid metabolism, attenuate hepatic steatosis and alleviate liver injury significantly. The excessive oxidative stress, high levels of inflammation and abnormal apoptosis in db/db mice were reversed after BBR intervention. BBR clearly changed the expression of AMP-activated protein kinase (AMPK)/Sirtuin 1 (SIRT1), and their downstream proteins. CONCLUSION:BBR could reverse NAFLD-related liver injury, likely by activating the AMPK/SIRT1 signaling pathway to inhibit oxidative stress, inflammation and apoptosis in hepatic tissue.

Following spinal cord injury, the inflammatory environment at the injury site causes local microglia and astrocytes to activate, which worsens the nerve damage in the affected area. Quercetin, an anti-inflammatory agent, has been limited in spinal cord injury due to its poor water solubility and easy degradation. Stem cell-derived extracellular vesicles can go through the blood-brain barrier and are an ideal drug delivery system. In this study, umbilical cord mesenchymal stem cell-derived extracellular vesicles were used to load quercetin to prevent its degradation and allow it to accumulate at the site of spinal cord injury. Our results showed that quercetin-loaded extracellular vesicles could inhibit the activation of microglia to M1 phenotype through the TLR4/NF-κB pathway, and the activation of astrocytes to A1 phenotype through the JAK2/STAT3 pathway. This reduced the production of inflammatory factors, mitigated neuronal damage, and inhibited the growth of astroglial scar, but promoted the recovery of motor function in rats with spinal cord injury.

BACKGROUND:Glioma, a malignant brain tumour, poses a significant threat to human life and well-being. Identifying new treatment targets is crucial. This study aimed to explore the impact of BRIP1 (BRCA1 interacting helicase 1) on glioma cell ferroptosis and its underlying mechanisms. METHODS:We utilized GEPIA (Gene Expression Profiling Interactive Analysis) to predict the expression of BRIP1 in glioma. The expression of BRIP1 was evaluated in normal brain glial cell lines (HEB) as well as two glioblastoma (GBM) cell lines (U87 and U251) using qRT-PCR (quantitative RT-PCR) and Western blot analyses. U251 cells were specifically chosen to investigate the impact of BRIP1 down-regulation and treatment with erastin (a ferroptosis activator) on cell viability and proliferation. In U251 cells, si-BRIP1 was administered in combination with the necroptosis inhibitor Necrostain-1 (Nec-1), apoptosis inhibitor Z-VAD-FMK (carbobenzoxy-valyl-alanyl-aspartyl- [O-methyl]-fluoromethylketone), autophagy inhibitor CQ (Chloroquine), pyroptosis inhibitor VX765 (Belnacasan), or ferroptosis inhibitor Fer-1 (ferrostain-1), as well as erastin+Fer-1, to determine the mode of programmed cell death using the CCK-8 (Cell counting kit-8) assay. Malondialdehyde (MDA) and glutathione (GSH) levels were measured using ELISA (Enzyme linked immunosorbent assay). Intracellular Fe2+ content was detected using a commercial reagent kit. Gpx4 (Glutathione peroxidase 4) levels were measured using Western blot analysis. The relationship between BRIP1 and SLC7A11 (Solute Carrier Family 7 Member 11) was verified by co-IP (co-immunoprecipitation) experiments. The level of SLC7A11 and SLC3A2 (Solute Carrier Family 3 Member 2) was analyzed through qRT-PCR and Western blot analyses. A rescue experiment was conducted to observe the effects of SLC7A11 overexpression on si-BRIP1-treated U251 cells. RESULTS:The GEPIA database predicted that the expression level of BRIP1 was increased in glioma. The expression level of BRIP1 was higher in U251 cells compared to HEB and U87 cells (p < 0.05). Both down-regulation of BRIP1 and treatment with erastin resulted in inhibited cell viability and proliferation in U251 cells (p < 0.05). The mode of programmed cell death in si-BRIP1-treated U251 cells was ferroptosis. Following si-BRIP1 transfection or erastin treatment, there was an increase in the levels of MDA and intracellular Fe2+ content, as well as a decrease in the levels of GSH, Gpx4, and SLC7A11 (p < 0.05). However, these alterations observed in the si-BRIP1 group were reversed by Fer-1 treatment (p < 0.05). The co-IP results demonstrated that BRIP1 and SLC7A11 were able to bind to each other. Up-regulation of SLC7A11 reversed the reduction in cell viability, the increase in MDA, the reduction in GSH, the increase in Fe2+ content, and the down-regulation of Gpx4 in si-BRIP1-treated U251 cells (p < 0.05). CONCLUSION:In this study, we found that down-regulation of BRIP1 could inhibit cell viability and proliferation in glioma cells through the induction of ferroptosis. This process was associated with increased oxidative stress, which was mediated by the down-regulation of SLC7A11 (xCT (Cysteine/glutamate transporter)) expression.

BACKGROUND:The combined treatment of transcatheter arterial chemoembolization (TACE) and apatinib had beneficial effects on the survival of patients with advanced hepatocellular carcinoma (HCC), but the efficacy of this regimen is still controversial and needs further investigation. MATERIALS AND METHODS:The clinical records of advanced HCC patients between May 2015 and December 2016 were collected from our hospital. They were categorized into the TACE monotherapy group and the combination of TACE and apatinib group. After propensity score matching (PSM) analysis, the disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and occurrence of adverse events were compared between the two treatments. RESULTS:There were 115 HCC patients included in the study. Among them, 53 received TACE monotherapy and 62 were treated with TACE plus apatinib. After PSM analysis, 50 pairs of patients were compared. The DCR of the TACE group was significantly lower than that of the combination of TACE and apatinib group (35 [70%] versus 45 [90%], P < 0.05). The ORR of the TACE group was also significantly lower than that of the combination of TACE and apatinib group (22 [44%] versus 34 [68%], P < 0.05). Patients who received the combined treatment of TACE and apatinib had longer PFS compared with those in the TACE monotherapy group ( P < 0.001). Moreover, hypertension, hand-foot syndrome, and albuminuria were more common in the combination of TACE and apatinib group ( P < 0.05), although all adverse events were well tolerated. CONCLUSIONS:The combined treatment of TACE and apatinib showed beneficial effects on tumor response, survival outcomes, and tolerance to treatment, which may be used as a routine regimen for advanced HCC patients.

The recovery and reconstruction of central nervous system function after spinal cord injury (SCI) is a worldwide problem. The difficulty lies in the feasibility issue of new axons passing through the injured area and the negative effect of scarring after injury. As a biological material, the human amniotic membrane (HAM) has the advantages of protecting nerve growth, inhibiting scar formation, and promoting neovascularization, but its weak physical properties are difficult to apply in treating SCI. In this study, HAMs were first decellularized and then chemically grafted with methacrylic anhydride. Next, the composite was photocrosslinked with gelatin methacrylate to prepare a cross-network biological complex. The final complexes prepared by appeal were used for in vitro and in vivo studies of SCI in rats, separately. In the in vitro experiment, the composite scaffold inherited abundant biological factors from the amniotic membrane and had the physical properties of a hydrogel, thus providing a favorable environment for the growth and development of neurons and blood vessels. In the in vivo experiment, the composite reduced scarring and promoted the growth of new nerves. Overall, the composite scaffolds can stably simulate the extracellular microenvironment in SCI defects, regulate pathological changes, and promote the generation of new neurons. Therefore, decellularized HAM hydrogels are promising biocomposite materials for central nerve repair after SCI.

After spinal cord injury (SCI), local inflammatory response and fibrous scar formation severely hinder nerve regeneration. Berberine (Ber) has a powerful regulatory effect on the local microenvironment, but its limited solubility and permeability through the blood-brain barrier severely limit its systemic efficacy. Human umbilical cord mesenchymal stem cells (hUC-MSCs)-derived small extracellular vesicles (sEVs) are natural nanocarriers with high cargo loading capacity, and can cross the blood-brain barrier. Most importantly, sEVs can improve drug solubility and drug utilization. Therefore, they can overcome many defects of Ber application. This experiment aimed to design a Ber-carrying hUC-MSCs-derived sEVs and GelMA hydrogel. Ber was loaded into sEVs (sEVs-Ber) by ultrasonic co-incubation with a drug loading capacity (LC) of 15.07%. The unhindered release of up to 80% of sEVs-Ber from GelMA hydrogel was accomplished for up to 14 days. And they could be directly absorbed by local cells of injury, allowing for direct local delivery of the drug and enhancing its efficacy. The experimental results confirmed injecting GelMA-sEVs-Ber into spinal cord defects could exert anti-inflammatory effects by regulating the expression of inflammatory factors. It also demonstrated the anti-fibrotic effect of Ber in SCI for the first time. The modulatory effects of sEVs and Ber on the local microenvironment significantly pro-moted nerve regeneration and recovery of motor function in post-SCI rats. These results demonstrated that the GelMA-sEVs-Ber dual carrier system is a promising therapeutic strategy for SCI repair.

BACKGROUND:Diabetic nephropathy (hereinafter referred to as DN) is one of the important causes of chronic renal failure, with great harm. We aimed to elucidate the role of transgelin-2, a key early detection for diabetic ne-phropathy.METHOD:The serum samples of 12 DN patients and 12 normal volunteers were collected for this experiment. Mice of the model group were injected intraperitoneally with streptozotocin following a high fat diet. Mouse podocyte (MPC5) cells were induced with 20 mmol/L d-glucose.RESULT:Transgelin-2 was highly expressed in DN patients with diabetic nephropathy both at the expression levels of mRNA and protein. Transgelin-2 expression was correlated with blood sugar in patients with DN. Transgelin-2 gene up-regulation enhanced inflammation and periostin levels, and reduced E-cadherin activity level in mice with DN. Over-expression of transgelin-2 increased inflammation and periostin levels, and reduced E-cadherin activity level in the in vitro model. Down-regulation of Transgelin-2 reduced inflammation and periostin levels and induced E-cadherin activity level in the in vitro model. Transgelin-2 induced ANXA2/ STAT3 signaling in a mouse model or an in vitro model. ANXA2 was one of the regulatory factors for the effects of transgelin-2 with inflammation, periostin, and E-cadherin in a model of DN.CONCLUSIONS:Taken together, these findings demonstrated that transgelin-2 promoted inflammation and periostin levels, and suppressed E-cadherin levels in DN by STAT3 signaling through ANXA2.

SARS-CoV-2 inhibitor plays an important role in COVID-19 preclinical drug discovery. As the existing SARS-COV-2 inhibitors showed more or less deficiencies, it is urgent to develop new SARS-COV-2 candidate inhibitors. De Novo Molecular Design plays a very important role in drug discovery. Most of the existing method use SMILES (Simplified Molecular Input Line Entry System) as the input of deep learning models. One popular way is utilizing deep learning models to automatically generate candidate drug molecules, and most of the existing models use SMILES as the input. In this study, we embed SMILES using a sub-word algorithm named BPE (Byte Pair Encoding) instead of One-Hot. First of all, the sub-word algorithm BPE learns a vocabulary of high frequency SMILES substrings from a large SMILES dataset, SMILES are then tokened according to the vocabulary learned by the BPE algorithm. Results show that the BPE algorithm can effectively learn the SMILES grammars and can help our generative model generate potential SARS-COV-2 inhibitors after transfer learning using the known 1253 SARS-COV-2 inhibitors. Generally, this paper provides an effectively method for de novo molecular design of SARS-COV-2 inhibitors.

Fatty liver is a highly heterogenous condition driven by various pathogenic factors in addition to the severity of steatosis. Protein insufficiency has been causally linked to fatty liver with incompletely defined mechanisms. Here we report that fatty liver is a sulfur amino acid insufficient state that promotes metabolic inflexibility via limiting coenzyme A availability. We demonstrate that the nutrient-sensing transcriptional factor EB synergistically stimulates lysosome proteolysis and methionine adenosyltransferase to increase cysteine pool that drives the production of coenzyme A and glutathione, which support metabolic adaptation and antioxidant defense during increased lipid influx. Intriguingly, mice consuming an isocaloric protein-deficient Western diet exhibit selective hepatic cysteine, coenzyme A and glutathione deficiency and acylcarnitine accumulation, which are reversed by cystine supplementation without normalizing dietary protein intake. These findings support a pathogenic link of dysregulated sulfur amino acid metabolism to metabolic inflexibility that underlies both overnutrition and protein malnutrition-associated fatty liver development.

To the Editor: Liver tumor may occur in any hepatic segment or lobe, and thus the liver resection is individualized as per the location and size of the tumor. In addition, the resection of the posterior and caudate lobes of the liver is especially difficult amongst all types of hepatectomy. Kawaguchi et al. believed that the laparoscopic resection of right posterior liver lobe was a difficult surgical procedure [1].

It is inevitable that scar formation occurs between the spinal dura and surrounding tissues after laminectomy. While extensive epidural fibrosis, which results in limited nerve root activity and severe pain, is the main cause of postoperative failed-back surgery syndrome. Novel biomaterial loading effective drugs based on reasonable design are eagerly needed for the safe and effective prevention of epidural adhesions. We filtrated a suitable dose of pirfenidone (PFD) to load hyaluronic acid methacryloyl (HAMA) hydrogel in vitro. And then, we compare PFD-loaded HAMA hydrogel with only using PFD or HAMA hydrogels after laminectomy by in vivo studies in rats. We describe a safe and efficient anti-adhesive PFD-loaded HAMA hydrogel that prevents epidural fibrosis through the stable and sustained release of PFD. It was shown that the PFD-loaded HAMA hydrogel effectively inhibited cell penetration and suppressed collagen I/III expression. Thus, it effectively prevented the formation of adhesions through pharmacological and physical processes. The PFD-loaded HAMA hydrogel can effectively prevent adhesion formation in both pharmacological and physical barrier effects.

Significance Hepatic insulin resistance is a well-recognized cause of hepatic glucose overproduction and fasting hyperglycemia in fatty liver disease and type-2 diabetes. Here, we have discovered that pharmacological inhibition of cullin neddylation by NAE1 inhibitor enhances hepatic insulin signaling and lowers blood glucose in mice. Hepatic neddylation inhibition delays cullin-RING E3 ligase–mediated insulin receptor substrate protein degradation and thus directly targets a key pathogenic defect underlying hepatic insulin resistance. This finding suggests that targeting cullin neddylation may be a potential therapeutic strategy for treating hyperglycemia.