Clinical significance of the modified Naples prognostic score in patients with stage II-III colon cancer undergoing curative resection: a retrospective study from the real world.

Background: The Naples prognostic score (NPS) determined by the nutritional and inflammatory condition of an individual is attracting growing attention for predicting postoperative outcomes in a variety of malignancies. The study aimed to assess the clinical significance of a modified NPS (M-NPS) and establish and validate nomograms incorporating M-NPS in curative stage II-III colon cancer patients. Methods: We retrospectively analyzed 328 stage II-III colon cancer patients receiving radical surgical resection at our hospital from January 2011 to December 2016. Kaplan-Meier (KM) survival analysis and Cox regression analysis were executed for overall survival (OS) and cancer-specific survival (CSS). Independent predictive indicators were applied to develop nomograms. The model's performance was evaluated using many different methods. Results: Of a total of 328 cases, 153 cases were in group 0, 145 in group 1, and 30 in group 2. In terms of OS or CSS, there were obvious differences between groups 0 and 1, and between groups 0 and 2. Age, obstruction, N stage, gross tumor type, and M-NPS group were independent prognostic indicators for OS, while obstruction, gross tumor type, M-NPS group, and N stage were independent predictive parameters for CSS. Furthermore, the training and validation sets were randomly allocated among a cohort of 328 patients. OS and CSS prediction nomograms were developed. In the training and validation cohort, the C-index and ROC analysis showed good discrimination, calibration curves exhibited an excellent level of consistency between model-predicted survival and actual survival outcomes, and DCA curves demonstrated good clinical performance. Conclusion: M-NPS is a reliable survival predictor in patients with curative stage II-III colon cancer. Nomograms incorporating M-NPS for OS and CSS have good predictive performance and clinical utility.

Palmitoylation regulates myelination by modulating the ZDHHC3-Cadm4 axis in the central nervous system.

The downregulation of Cadm4 (Cell adhesion molecular 4) is a prominent feature in demyelination diseases, yet, the underlying molecular mechanism remains elusive. Here, we reveal that Cadm4 undergoes specific palmitoylation at cysteine-347 (C347), which is crucial for its stable localization on the plasma membrane (PM). Mutation of C347 to alanine (C347A), blocking palmitoylation, causes Cadm4 internalization from the PM and subsequent degradation. In vivo experiments introducing the C347A mutation (Cadm4-KI) lead to severe myelin abnormalities in the central nervous system (CNS), characterized by loss, demyelination, and hypermyelination. We further identify ZDHHC3 (Zinc finger DHHC-type palmitoyltransferase 3) as the enzyme responsible for catalyzing Cadm4 palmitoylation. Depletion of ZDHHC3 reduces Cadm4 palmitoylation and diminishes its PM localization. Remarkably, genetic deletion of ZDHHC3 results in decreased Cadm4 palmitoylation and defects in CNS myelination, phenocopying the Cadm4-KI mouse model. Consequently, altered Cadm4 palmitoylation impairs neuronal transmission and cognitive behaviors in both Cadm4-KI and ZDHHC3 knockout mice. Importantly, attenuated ZDHHC3-Cadm4 signaling significantly influences neuroinflammation in diverse demyelination diseases. Mechanistically, we demonstrate the predominant expression of Cadm4 in the oligodendrocyte lineage and its potential role in modulating cell differentiation via the WNT-ß-Catenin pathway. Together, our findings propose that dysregulated ZDHHC3-Cadm4 signaling contributes to myelin abnormalities, suggesting a common pathological mechanism underlying demyelination diseases associated with neuroinflammation.

The pH-sensitive translocation of V-ATPase in the small airway of cystic fibrosis pigs.

In contrast to pig large airways, the pH of airway surface liquid (ASL) in pig small airways is regulated by CFTR mediated HCO-3 secretion and the vacuolar-type H+ ATPase (V-ATPase) proton secretion. We hypothesized that in Cystic Fibrosis (CF), the ASL pH of small airways is acidic, and the V-ATPase is internalized. We quantified proton secretion during the addition of an alkaline test solutions by measuring changes in a pH dependent fluorescent dye generated by porcine small airway epithelia in the absence and presence of bafilomycin A1. The pH-dependent translocation of V-ATPase in ex vivo and in vivo preparations was measured using immunolocalization of V-ATPase. We found that bafilomycin sensitive proton secretion stopped when the ASL pH was less than 7.10. In non-CF pigs and mice, we found that V-ATPase was localized in the apical membrane, and internalized when the lungs were instilled with a pH 6.8 solution.Studies where we immediately fixed lungs from pigs revealed apical V-ATPase detection in non-CF piglets and less apical detection in CF piglets. Our data suggest that V-ATPase in small airways is internalized when the ASL pH is acidic. The decrease in apical localization of V-ATPase in CF pigs is consistent with an acidic ASL pH.

Smart hydrogel composite for microenvironmental humidity regulation in cigar storage.

Environmental humidity profoundly influences various life activities, especially for plants that depend heavily on optimal humidity for growth. The humidity index is particularly crucial for preserving the functionality of plant leaves, notably in economically valuable plants such as cigar tobacco. This paper introduces a novel dual-layer moisturizing material, a PAS-PDMS composite, based on polyacrylamide/solketal (PAS) hydrogel and polydimethylsiloxane (PDMS). This material features a unique hierarchical water release mechanism. Comprehensive analyses, including thermogravimetric analysis, Fourier-transform infrared spectroscopy, low-field nuclear magnetic resonance, and dynamic water adsorption studies, confirm the water migration and humidity control mechanisms of the PAS-PDMS composite. This smart hydrogel composite regulates microenvironmental humidity bidirectionally. When applied to cigar boxes for storage, it stabilizes internal humidity at approximately 65%, maintaining this level for over 20 days. Furthermore, the PAS-PDMS composite exhibits superior mechanical properties and light transmittance, achieving an exceptional transmittance of 84%. In conclusion, the PAS-PDMS composite offers intelligent humidity control, providing a novel approach to the storage and preservation of cigars.

Early decompressive surgery improves long-term prognosis in patients with intracerebral hemorrhage.

BACKGROUND: Multiple studies have shown that early decompressive surgery in patients with intracerebral hemorrhage can effectively limit hematoma expansion, reduce perihematomal edema, and improve prognosis. However, these studies are limited by small sample sizes and short follow-up times. OBJECTIVE: To analyze the effect of early decompressive surgery on the long-term prognosis of patients with cerebral hemorrhage and identify the influencing factors for poor prognosis. METHODS: A retrospective analysis of 78 patients with cerebral hemorrhage admitted between January 2020 and December 2022 was conducted. Patients were divided into early and delayed surgery groups for comparison of outcomes such as mortality rate, modified Rankin Scale score, and Short Form-36 scores. Additionally, factors influencing long-term prognosis were analyzed through logistic regression based on significant differences observed between groups. RESULTS: The early decompressive surgery group showed superior outcomes with lower mortality rates, modified Rankin Scale (mRS) scores, hematoma expansion rates, and perihematomal edema volumes compared to the delayed surgery group (P< 0.05). Additionally, age, preoperative Glasgow Coma Scale (GCS) score, preoperative hematoma volume, and a history of hypertension or diabetes were identified as independent prognostic factors for patients with cerebral hemorrhage, with odds ratios (ORs) greater than 1. CONCLUSIONS: Early decompressive surgery can improve the long-term prognosis and quality of life of patients with cerebral hemorrhage, reduce mortality rates, and decrease hematoma expansion and perihematomal edema. Older patients, those with higher preoperative hematoma volume and GCS score, and those with coexisting hypertension and diabetes should be given special attention to decrease the occurrence of adverse prognosis.

Phase separation of RNF214 promotes the progression of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, and the expression and function of an uncharacterized protein RNF214 in HCC are still unknown. Phase separation has recently been observed to participate in the progression of HCC. In this study, we investigated the expression, function, and phase separation of RNF214 in HCC. We found that RNF214 was highly expressed in HCC and associated with poor prognosis. RNF214 functioned as an oncogene to promote the proliferation, migration, and metastasis of HCC. Mechanically, RNF214 underwent phase separation, and the coiled-coil (CC) domain of RNF214 mediated its phase separation. Furthermore, the CC domain was necessary for the oncogenic function of RNF214 in HCC. Taken together, our data favored that phase separation of RNF214 promoted the progression of HCC. RNF214 may be a potential biomarker and therapeutic target for HCC.

The diagnostic value of MRI-based vertebral bone quality score for osteoporosis or osteopenia in patients undergoing lumbar surgery: a meta-analysis.

The importance of osteoporosis assessment before lumbar surgery is well recognized. The MRI-based Vertebral Bone Quality (VBQ) score is introduced to evaluate bone quality; however, its diagnostic value has not been well documented. The purpose of this meta-analysis was to summarize the diagnostic value of the VBQ score for osteoporosis or osteopenia in patients undergoing lumbar surgery. We comprehensively searched electronic databases for studies exploring the diagnostic accuracy of the VBQ score for osteoporosis/osteopenia in patients with lumbar disease following the PRISMA guidelines. The quality of the included studies was assessed. The VBQ scores were compared between the groups, and the pooled sensitivity, specificity, and summary receiver operating characteristic (ROC) were calculated. Publication bias was assessed, and meta-regression was conducted. We included 17 studies with a total of 2815 patients, with a mean age of 66.4 years and a percentage of females of 72.5%. According to the QUADAS-2 tool, the quality of the included studies was relatively high. The results showed a significantly higher VBQ score in the osteoporosis/osteopenia group compared with the control group. According to the mean VBQ cutoff value of 3.02 ± 0.38 for the diagnosis of osteoporosis, the pooled sensitivity and specificity were 0.76 and 0.74, respectively, and the AUC was 0.81. According to the mean VBQ cutoff value of 2.31 ± 0.18 for the diagnosis of osteopenia, the pooled sensitivity and specificity were 0.78 and 0.58, respectively, and the AUC was 0.76. The MRI-based VBQ score could provide useful information for identifying patients with low bone mass who need further evaluation. Future prospective studies are still needed to evaluate the complementary role of the VBQ score.

Identification of a novel apoptosis-related genes signature to improve gastric cancer prognosis prediction.

Dysregulation of apoptosis occurs in different types of malignant tumors and is likely to influence the tumor evolution, as well as clinical prognosis. However, the limited number of studies investigating the predictive power of apoptosis-related genes (ARGs) in gastric cancer indicates a gap in the current research. 174 ARGs who differentially expressed were screened using public databases, including the Gene Expression Omnibus and the Molecular Signatures Database. Univariate and LASSO regression analyses were rigorous approaches to recognize the 12 optimal genes (CTHRC1, PDGFRL, VCAN, GJA1, LOX, UPP1, ANGPT2, CRIM1, HIF1A, APOD, RNase1, and ID1) that make up the prognostic risk model. Molecular mutations, related signaling pathways, and immune system characteristics in different subgroups defined by the risk model were analyzed using different R packages. Moreover, based on the database of Genomics of Drug Sensitivity in Cancer, chemotherapy sensitivity was predicted among the risk subgroups. As a result, there were differences in mutation profiles, signaling pathways, and infiltrated immune cells between patients in various risk groups. Moreover, the low-risk group displayed greater sensitivity to chemotherapy than the high-risk group. Risk model provided a better prognostic value than the T, N, and M stages, according to the receiver operating characteristic curve. Finally, in a nomogram, the risk model and clinical factors were combined to visualize the survival rates of patients with GC. In response to the differential expression of apoptosis-related genes, a novel model for predicting the prognosis of GC patients was developed. This model may be highly valuable for guiding doctors to deliver treatment plans tailored to the need of patients with GC.

Genome-wide selection reveals candidate genes associated with multiple teats in Hu sheep.

Increasing the number of teats in sheep helps to improve the survival rate of sheep lambs after birth. In order to analyze the candidate genes related to the formation of multiple teats in Hu sheep, the present study was conducted to investigate the genetic pattern of multiple teats in Hu sheep. In this study, based on genome-wide data from 157 Hu sheep, Fst, xp-EHH, Pi and iHS signaling were performed, and the top 5% signal regions of each analyzed result were annotated based on the Oar_v4.0 for sheep. The results show that a total of 142 SNP loci were selected. We found that PTPRG, TMEM117 and LRP1B genes were closely associated with polypodium formation in Hu sheep, in addition, among the candidate genes related to polypodium we found genes such as TMEM117, SLC25A21 and NCKAP5 related to milk traits. The present study screened out candidate genes for the formation of multiple teats at the genomic level in Hu sheep.

Synthesis of All-Benzene Multi-Macrocyclic Nanocarbons by Post-Functionalization of meta-Cycloparaphenylenes.

Expanding the diversity of multi-macrocyclic nanocarbons, particularly those with all-benzene scaffolds, represents intriguing yet challenging synthetic tasks. Complementary to the existing synthetic approaches, here we report an efficient and modular post-functionalization strategy that employs iridium-catalyzed C-H borylation of the highly strained meta-cycloparaphenylenes (mCPPs) and an mCPP-derived catenane. Based on the functionalized macrocyclic synthons, a number of novel all-benzene topological structures including linear and cyclic chains, polycatenane, and pretzelane have been successfully prepared and characterized, thereby showcasing the synthetic utility and potential of the post-functionalization strategy.

Dorsomorphin attenuates ABCG2-mediated multidrug resistance in colorectal cancer.

Colorectal cancer is a common malignant tumor with high mortality, for which chemotherapy resistance is one of the main reasons. The high expression of ABCG2 in the cancer cells and expulsion of anticancer drugs directly cause multidrug resistance (MDR). Therefore, the development of new ABCG2 inhibitors that block the active causes of MDR may provide a strategy for the treatment of colorectal cancer. In this study, we find that dorsomorphin (also known as compound C or BML-275) potently inhibits the transporter activity of ABCG2, thereby preserving the chemotherapeutic agents mitoxantrone and doxorubicin to antagonize MDR in ABCG2-overexpressing colorectal cancer cells. Additionally, dorsomorphin does not alter ABCG2 protein expression. The results of molecular docking studies show that dorsomorphin is bound stably to the ABCG2-binding pocket, suggesting that dorsomorphin is a potent ABCG2 inhibitor that attenuates ABCG2-mediated MDR in colorectal cancer.

Ultra-pH-sensitive nanoparticle of gambogenic acid for tumor targeting therapy via anti-vascular strategy plus immunotherapy.

Although the combination of anti-vascular strategy plus immunotherapy has emerged as the optimal first-line treatment of hepatocellular carcinoma, lack of tumor targeting leads to low antitumor efficacy and serious side effect. Here, we report an ultra-pH-sensitive nanoparticle of gambogenic acid (GNA) encapsulated by poly(ethylene glycol)-poly(2-azepane ethyl methacrylate) (PEG-PAEMA) for tumor-targeting combined therapy of anti-vascular strategy plus immunotherapy. PEG-PAEMA-GNA nanoparticle was quite stable at pH 7.4 for 30 d. In contrast, it exerted size shrinkage, charge reversal and the release of GNA at pH 6.7 within 24 h. Moreover, PEG-PAEMA-GNA significantly enhanced the anti-vascular activity, membrane-disruptive capability and pro-apoptosis when pH changed from 7.4 to 6.7. Western blot analysis exhibits that PEG-PAEMA and its GNA nanoparticle facilitated the phosphorylation of STING protein. In vivo assays show that PEG-PAEMA-GNA not only displayed much higher tumor inhibition of 92 % than 37 % of free GNA, but also inhibited tumor vasculature, promoted the maturation of dendritic cells and recruited more cytotoxic t-lymphocytes for sufficient anti-vascular therapy and immunotherapy. All these results demonstrate that PEG-PAEMA-GNA displayed tumor-targeting combined treatment of anti-vascular therapy and immunotherapy. This study offers a simple and novel method for the combination of anti-vascular therapy and immunotherapy with high selectivity towards tumor.

The Oncolytic virus VT1092M and an Anti-PD-L1 antibody synergize to induce systemic antitumor immunity in a murine bilateral tumor model.

This study investigated the synergistic potential of an oncolytic herpes simplex virus armed with interleukin 12 (VT1092M) in combination with immune checkpoint inhibitors for enhancing antitumor responses. The potential of this combination treatment to induce systemic antitumor immunity was assessed using bilateral subcutaneous tumor and tumor re-challenge mouse models. The antitumor efficacy of various OV and ICI treatment combinations and the underlying mechanisms were explored through diverse analytical techniques, including flow cytometry and RNA sequencing. Using VT1092M, either alone or in combination with an anti-PD-L1 antibody, significantly reduced the sizes of both the injected and untreated abscopal tumors in a bilateral tumor mouse model. The combination therapy demonstrated superior antitumor efficacy to the other treatment conditions tested, which was accompanied by an increase in T cell numbers and CD8+T cell activation. Results from the survival and tumor re-challenge experiments showed that the combination therapy elicited long-term, tumor-specific immune responses, which were associated with tumor clearance and prolonged survival. Immune cell depletion assays identified CD8+T cells as the crucial mediators of systemic antitumor immunity during combination therapy. In conclusion, the combination of VT1092M and PD-L1 blockade emerged as a potent inducer of antitumor immune responses, surpassing the efficacy of each monotherapy. This synergistic approach holds promise for achieving robust and sustained antitumor immunity, with potential implications for preventing tumor metastasis in patients with cancer.

Identifying potential (re)hemorrhage among sporadic cerebral cavernous malformations using machine learning.

The (re)hemorrhage in patients with sporadic cerebral cavernous malformations (CCM) was the primary aim for CCM management. However, accurately identifying the potential (re)hemorrhage among sporadic CCM patients in advance remains a challenge. This study aims to develop machine learning models to detect potential (re)hemorrhage in sporadic CCM patients. This study was based on a dataset of 731 sporadic CCM patients in open data platform Dryad. Sporadic CCM patients were followed up 5 years from January 2003 to December 2018. Support vector machine (SVM), stacked generalization, and extreme gradient boosting (XGBoost) were used to construct models. The performance of models was evaluated by area under receiver operating characteristic curves (AUROC), area under the precision-recall curve (PR-AUC) and other metrics. A total of 517 patients with sporadic CCM were included (330 female [63.8%], mean [SD] age at diagnosis, 42.1 [15.5] years). 76 (re)hemorrhage (14.7%) occurred during follow-up. Among 3 machine learning models, XGBoost model yielded the highest mean (SD) AUROC (0.87 [0.06]) in cross-validation. The top 4 features of XGBoost model were ranked with SHAP (SHapley Additive exPlanations). All-Elements XGBoost model achieved an AUROCs of 0.84 and PR-AUC of 0.49 in testing set, with a sensitivity of 0.86 and a specificity of 0.76. Importantly, 4-Elements XGBoost model developed using top 4 features got a AUROCs of 0.83 and PR-AUC of 0.40, a sensitivity of 0.79, and a specificity of 0.72 in testing set. Two machine learning-based models achieved accurate performance in identifying potential (re)hemorrhages within 5 years in sporadic CCM patients. These models may provide insights for clinical decision-making.

Exosome/antimicrobial peptide laden hydrogel wound dressings promote scarless wound healing through miR-21-5p-mediated multiple functions.

Mesenchymal stem cell (MSC)-based therapy is an effective strategy for regenerative therapy. However, safety and ease of use are still issues to be overcome in clinical applications. Exosomes are naturally derived nanoparticles containing bioactive molecules, which serve as ideal cell-free therapeutic modalities. However, issues such as delivery, long-term preservation and activity maintenance of exosomes are other problems that limit their application. In this study, we proposed the use of rapid freeze-dry-thaw macroporous hydrogels for the encapsulation of HucMSC-derived exosomes (HucMSC-Exos) combined with an antimicrobial peptide coating. This exosome-encapsulated hyaluronic acid macroporous hydrogel HD-DP7/Exo can achieve long-term storage and transport by lyophilization and can be rapidly redissolved for treatment. After comprehensively comparing the therapeutic effects of HucMSC-Exos and HucMSC-loaded hydrogels, we found that HucMSC-Exos could also effectively regulate fibroblasts, vascular endothelial cells, and macrophages and inhibit myofibroblast-mediated fibrosis, thus promoting tissue regeneration and inhibiting scar formation in a mouse model of deep second-degree burn infection healing. These properties of lyophilized storage and whole-process-repair make HD-DP7/Exo have potential application value and application prospects.

FXR controls duodenogastric reflux-induced gastric inflammation through negatively regulating ER stress-associated TNXIP/NLPR3 inflammasome.

Duodenogastric reflux (DGR) is closely associated with gastric inflammation and tumorigenesis; however, the precise mechanism is unclear. Hence, we aim to clarify this molecular mechanism and design an effective therapeutic strategy based on it. The present study found that DGR induced TXNIP/NLRP3 inflammasome activation and triggered pyroptosis in gastric mucosa in vitro and in vivo, in which endoplasmic reticulum (ER) stress via PERK/eIF2α/CHOP signaling was involved. Mechanistically, farnesoid X receptor (FXR) antagonized the DGR-induced PERK/eIF2α/CHOP pathway and reduced TXNIP and NLRP3 expression. Moreover, FXR suppressed NLRP3 inflammasome activation by physically interacting with NLRP3 and caspase-1. Administration of the FXR agonist OCA protected the gastric mucosa from DGR-induced barrier disruption and mucosal inflammation. In conclusion, our study demonstrates the involvement of TXNIP/NLRP3 inflammasome-mediated pyroptosis in DGR-induced gastric inflammation. FXR antagonizes gastric barrier disruption and mucosal inflammation induced by DGR. Restoration of FXR activity may be a therapeutic strategy for DGR-associated gastric tumorigenesis.

Small-molecule agents for cancer immunotherapy.

Cancer immunotherapy, exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy, is revolutionizing cancer therapy. They induce long-term tumor regression and overall survival benefit in many types of cancer. With the advances in our knowledge about the tumor immune microenvironment, remarkable progress has been made in the development of small-molecule drugs for immunotherapy. Small molecules targeting PRR-associated pathways, immune checkpoints, oncogenic signaling, metabolic pathways, cytokine/chemokine signaling, and immune-related kinases have been extensively investigated. Monotherapy of small-molecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance. Here, we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.

USP50 regulates NLRP3 inflammasome activation in duodenogastric reflux-induced gastric tumorigenesis.

Duodenogastric reflux (DGR) has been linked to the onset of gastric cancer (GC), although the precise mechanism is yet obscure. Herein, we aimed to investigate how refluxed bile acids (BAs) and macrophages are involved in gastric carcinogenesis. In both active human bile reflux gastritis and the murine DGR model, ubiquitin specific protease 50 (USP50) was dramatically raised, and macrophages were the principal leukocyte subset that upregulated USP50 expression. Enhancing USP50 expression amplified bile acid-induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and subsequent high-mobility group box protein 1 (HMGB1) release, while USP50 deficiency resulted in the reversed alteration. Mechanistically, USP50 interacted with and deubiquitinated apoptosis-associated speck-like protein containing CARD (ASC) to activate NLRP3 inflammasome. The release of HMGB1 contributes to gastric tumorigenesis by PI3K/AKT and MAPK/ERK pathways. These results may provide new insights into bile reflux-related gastric carcinogenesis and options for the prevention of DGR-associated GC.

Evodiamine inhibits growth of vemurafenib drug-resistant melanoma via suppressing IRS4/PI3K/AKT signaling pathway.

Evodiamine, a novel alkaloid, was isolated from the fruit of tetradium. It exerts a diversity of pharmacological effects and has been used to treat gastropathy, hypertension, and eczema. Several studies reported that evodiamine has various biological effects, including anti-nociceptive, anti-bacterial, anti-obesity, and anti-cancer activities. However, there is no research regarding its effects on drug-resistant cancer. This study aimed to investigate the effect of evodiamine on human vemurafenib-resistant melanoma cells (A375/R cells) proliferation ability and its mechanism. Cell activity was assessed using the cell counting kit-8 (CCK-8) method. Flow cytometry assay was used to assess cell apoptosis and cell cycle. A xenograft model was used to analyze the inhibitory effects of evodiamine on tumor growth. Bioinformatics analyses, network pharmacology, and molecular docking were used to explore the potential mechanism of evodiamine in vemurafenib-resistant melanoma. RT-qPCR and Western blotting were performed to reveal the molecular mechanism. The alkaloid extract of the fruit of tetradium, evodiamine showed the strongest tumor inhibitory effect on vemurafenib-resistant melanoma cells compared to treatment with vemurafenib alone. Evodiamine inhibited vemurafenib-resistant melanoma cell growth, proliferation, and induced apoptosis, conforming to a dose-effect relationship and time-effect relationship. Results from network pharmacology and molecular docking suggested that evodiamine might interact with IRS4 to suppress growth of human vemurafenib-resistant melanoma cells. Interestingly, evodiamine suppressed IRS4 expression and then inhibited PI3K/AKT signaling pathway, and thus had the therapeutic action on vemurafenib-resistant melanoma.