CDKN1A promotes Cis-induced AKI by inducing cytoplasmic ROS production and ferroptosis.

BACKGROUND AND OBJECTIVE: This study focuses on investigating the role of CDKN1A in cisplatin-induced AKI (acute kidney injury, AKI) and its potential as a biomarker for early diagnosis and therapeutic intervention by integrating bioinformatics analysis, machine learning, and experimental validation. METHODS: We analyzed the GSE85957 dataset to find genes that changed between control and cisplatin-treated rats. Using bioinformatics and machine learning, we found 13 important genes related to ferroptosis and the P53 pathway. The key gene, CDKN1A, was identified using various algorithms. We then tested how reducing CDKN1A in human kidney cells affected cell health, ROS, and iron levels. We also checked how CDKN1A changes the levels of proteins linked to ferroptosis using Q-PCR and Western Blot. RESULTS: CDKN1A was found to negatively regulate the G1/S phase transition and was associated with ferroptosis in p53 signaling. Experiments in human renal tubular epithelial cells (HK-2) and rat NRK-52E cells showed that CDKN1A knockdown mitigated cisplatin-induced cell injury by reducing oxidative stress and ferroptosis. CONCLUSION: Our integrated approach identified CDKN1A as a biomarker for cisplatin-induced AKI. Its regulation could be key in AKI pathogenesis, offering new therapeutic insights and aiding in early diagnosis and intervention.

Artemisitene induces apoptosis of breast cancer cells by targeting FDFT1 and inhibits the growth of breast cancer patient-derived organoids.

Artemisitene (ATT) is a natural bioactive compound with anti-breast cancer activity. However, the direct target and clinical efficacy of ATT on breast cancer are still unclear. The current study aimed to identify the target protein and underlying mechanism of ATT in anti-breast cancer. Moreover, patient-derived organoids (PDOs) were employed to assess the clinical efficacy of ATT on breast cancer. Herein, molecular docking, molecular dynamics simulation, cellular thermal shift assay (CETSA) combined with Western blot, surface plasmon resonance (SPR) were applied to confirm the interactional target of ATT in breast cancer cells. Bioinformatics analysis, Western blot, flow cytometry, plasmid construction and lentivirus infection, chromatin immunoprecipitation (ChIP) assay, and quantitative real-time PCR (RT-qPCR) were performed to reveal the potential mechanism of ATT in treating breast cancer. PDOs were established to evaluate the clinical therapeutic efficiency of ATT on breast cancer. We found that ATT interacted with Farnesyl-diphosphate farnesyltransferase 1 (FDFT1) in breast cancer cells. Knockdown of FDFT1 induced NEDD4 expression and apoptosis in breast cancer cells. Overexpression of FDFT1 could rescue ATT-induced apoptosis, while interfering with FDFT1 expression decreased the level of RelA (NF-κB p65 subunit) in the nucleus in breast cancer cells. Knockdown of FDFT1 induced NEDD4 expression by regulating TNFR1/NF-κB pathway. Overexpression of FDFT1 could reverse the activation of ATT-induced TNFR1/NF-κB/NEDD4 pathway in breast cancer cells. Interestingly, the ChIP assay and RT-qPCR revealed that p65 could regulate NEDD4 transcription. Furthermore, ATT exhibited a broad-spectrum inhibitory effect on the growth of breast cancer PDOs with different pathological subtypes, and showed an excellent safety profile in comparison with that of conventional chemotherapy drugs. In summary, this work demonstrated that ATT targets FDFT1 to induce apoptosis of breast cancer cells through regulating TNFR1/NF-κB/NEDD4 pathway and suppresses breast cancer PDOs growth, which supported ATT as an effective and potential drug candidate for breast cancer treatment.

Chicoric acid acts as an ALOX15 inhibitor to prevent ferroptosis in asthma.

BACKGROUND: Chicoric acid (CA) is a crucial immunologically active compound found in chicory and echinacea, possessing a range of biological activities. Ferroptosis, a type of iron-dependent cell death induced by lipid peroxidation, plays a key role in the development and advancement of asthma. Targeting ferroptosis could be a potential therapeutic strategy for treating asthma. PURPOSE: The purpose of this study was to explore the screening of ALOX15, a pivotal target of ferroptosis in asthma, and potential therapeutic agents, as well as to investigate the promising potential of CA as an ALOX15 inhibitor for modulating ferroptosis in asthma. METHODS: Through high-throughput data processing of bronchial epithelial RNA from asthma patients using bioinformatics and machine learning, the key target of ferroptosis in asthma, ALOX15, was identified. An inhibitor of ALOX15 was then obtained through high-throughput molecular docking and molecular dynamics simulation tests. In vitro experiments were conducted using a 16HBE cell model induced by house dust mite (HDM) and lipopolysaccharide (LPS), which were treated with the ALOX15 inhibitor (PD146176), CA treatment, or ALOX15 knockdown. In vivo experiments were also carried out using a mouse model induced by HDM and LPS. RESULTS: The composite model of ALOX15 and CA in molecular dynamics simulations shows good stability and flexibility. Network pharmacological analysis reveals that CA regulates ferroptosis through ALOX15 in treating asthma. In vitro studies show that ALOX15 is highly expressed in HDM and LPS treatments, while CA inhibits HDM and LPS-induced ferroptosis in 16HBE cells by reducing ALOX15 expression. Knockdown of ALOX15 has the opposite effect. Metabolomics analysis identifies key compounds associated with ferroptosis, including L-Targinine, eicosapentaenoic acid, 16-hydroxy hexadecanoic acid, and succinic acid. In vivo experiments demonstrate that CA suppresses ALOX15 expression, inhibits ferroptosis, and improves asthma symptoms in mice. CONCLUSION: Our research initially identified CA as a promising asthma treatment that effectively blocks ferroptosis by specifically targeting ALOX15. This study not only highlights CA as a potential therapeutic agent for asthma but also introduces novel targets and treatment options for this condition, along with innovative approaches for utilizing natural compounds to target diseases associated with ferroptosis.

Asiatic acid induces lung cancer toxicity by triggering SRC-mediated ferroptosis.

Ferroptosis is a recently discovered form of regulated cell death that shows promise as a novel approach for inducing tumor cell death in cancer treatment, with significant research potential. Asiatic acid (AA), a key component of the traditional Chinese medicine Centella asiatica, has been identified as having potential therapeutic benefits for various diseases, particularly cancer. Non-small cell lung cancer (NSCLC) is a challenging and prevalent form of cancer to treat. In our study, we utilized network pharmacology, molecular docking, and experimental methods to investigate the potential of AA in treating NSCLC and to elucidate its role in inhibiting cancer through the ferroptosis pathway. Through network pharmacology analysis, we identified that AA targets the core NSCLC protein SRC through the ferroptosis pathway. Our experiments demonstrated that treatment with AA led to increased iron accumulation, mitochondrial membrane potential, and expression of ferroptosis markers glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and acyl-CoA synthetase long chain family member 4 (ACSL4) in NSCLC cells, confirming the induction of ferroptosis. In conclusion, AA has the potential to target SRC and induce NSCLC cell death through the ferroptosis pathway, offering a promising approach for cancer treatment.

Targeting ferroptosis in autoimmune diseases: Mechanisms and therapeutic prospects.

Ferroptosis is a form of regulated cell death that relies on iron and exhibits unique characteristics, including disrupted iron balance, reduced antioxidant defenses, and abnormal lipid peroxidation. Recent research suggests that ferroptosis is associated with the onset and progression of autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and multiple sclerosis (MS). However, the precise effects and molecular mechanisms remain incompletely understood. This article presents an overview of how ferroptosis mechanisms contribute to the development and advancement of autoimmune diseases, as well as the involvement of various immune cells in linking ferroptosis to autoimmune conditions. It also explores potential drug targets within the ferroptosis pathway and recent advancements in therapeutic approaches aimed at preventing and treating autoimmune diseases by targeting ferroptosis. Lastly, the article discusses the challenges and opportunities in utilizing ferroptosis as a potential therapeutic avenue for autoimmune disorders.

Identification of Marine-Derived SLC7A11 Inhibitors: Molecular Docking, Structure-Based Virtual Screening, Cytotoxicity Prediction, and Molecular Dynamics Simulation.

The search for anticancer drugs that target ferroptosis is a promising avenue of research. SLC7A11, a key protein involved in ferroptosis, has been identified as a potential target for drug development. Through screening efforts, novel inhibitors of SLC7A11 have been designed with the aim of promoting ferroptosis and ultimately eliminating cancer cells. We initially screened 563 small molecules using pharmacophore and 2D-QSAR models. Molecular docking and ADMET toxicity predictions, with Erastin as a positive control, identified the small molecules 42711 and 27363 as lead compounds with strong inhibitory activity against SLC7A11. Further optimization resulted in the development of a new inhibitor structure (42711_11). Molecular docking and ADMET re-screening demonstrated successful fragment substitution for this small molecule. Final molecular dynamics simulations also confirmed its stable interaction with the protein. These findings represent a significant step towards the development of new therapeutic strategies for ferroptosis-related diseases.

Six transmembrane epithelial antigens of the prostate to illustrate inflammatory response in gastrointestinal cancers.

Gastrointestinal cancer (GIC) is a common and widespread form of tumor, with colonoscopy and upper gastrointestinal endoscopy available to detect relevant precancerous polyps and lesions. However, many patients are already in the late stages when first diagnosed with such cancer, resulting in a poor prognosis. Thus, it is necessary to explore new methods and research directions in order to improve the treatment of GIC. Given the specific nature of the gastrointestinal tract, research should focus on the mechanisms of various inflammations and the interactions between food entering and exiting from the gastrointestinal tract and cancer cells. Interestingly, six transmembrane epithelial antigens of the prostates (STEAPs) have been found to be significantly linked to the progression of malignant tumors, associated with intracellular oxidative stress and playing a major role in inflammation with their structure and function. This paper explores the mechanism of STEAPs in the inflammatory response of GIC, providing a theoretical basis for the prevention and early intervention of GIC. The basic properties of the STEAP family as metal reductase are also explained. When it comes to intervention for GIC prevention, STEAPs can affect the activity of Fe3+, Cu2+ reductase and regulate metal ion uptake in vivo, participating in inflammation-related iron and copper homeostasis. Thus, the mechanism of STEAPs on inflammation is of important value in the prevention of GIC.

An overview of the contemporary diagnosis and management approaches for anaplastic thyroid carcinoma.

Thyroid carcinoma is a complex disease with several types, the most common being well-differentiated and undifferentiated. The latter, "undifferentiated carcinoma", also known as anaplastic thyroid carcinoma (ATC), is a highly aggressive malignant tumor accounting for less than 0.2% of all thyroid carcinomas and carries a poor prognosis with a median survival of 5 months. BRAF gene mutations are the most common molecular factor associated with this type of thyroid carcinoma. Recent advances in targeted biological agents, immunotherapy, stem cell therapy, nanotechnology, the dabrafenib/trametinib combination therapy, immune checkpoint inhibitors (ICI) and artificial intelligence offer novel treatment options. The combination therapy of dabrafenib and trametinib is the current standard treatment for patients with BRAF-V600E gene mutations. Besides, the dabrafenib/trametinib combination therapy, ICI, used alone or in combination with targeted therapies have raised some hopes for improving the prognosis of this deadly disease. Younger age, earlier tumor stage and radiotherapy are all prognostic factors for improved outcomes. Ultimately, therapeutic regimens should be tailored to the individual patient based on surveillance and epidemiological data, and a multidisciplinary approach is essential.

New targets for cancer promotion and therapy in gliomas: Scinderin.

Glioma is one of the most common primary intracranial tumors, characterized by invasive growth and poor prognosis. Actin cytoskeletal rearrangement is an essential event in tumor cell migration. Scinderin (SCIN), an actin severing and capping protein that regulates the actin cytoskeleton, is involved in the proliferation and migration of certain cancer cells. However, its biological role and molecular mechanism in glioma remain unclear. Lin et al explored the role and mechanism of SCIN in gliomas. The results showed that SCIN mechanically affected cytoskeleton remodeling and inhibited the formation of lamellipodia via RhoA/FAK signaling pathway. This study identifies the cancer-promoting role of SCIN and provides a potential therapeutic target for SCIN in glioma treatment.

Ferroptosis crosstalk in anti-tumor immunotherapy: molecular mechanisms, tumor microenvironment, application prospects.

Immunotherapies for cancer, specifically immune checkpoint inhibition (ICI), have shown potential in reactivating the body's immune response against tumors. However, there are challenges to overcome in addressing drug resistance and improving the effectiveness of these treatments. Recent research has highlighted the relationship between ferroptosis and the immune system within immune cells and the tumor microenvironment (TME), suggesting that combining targeted ferroptosis with immunotherapy could enhance anti-tumor effects. This review explores the potential of using immunotherapy to target ferroptosis either alone or in conjunction with other therapies like immune checkpoint blockade (ICB) therapy, radiotherapy, and nanomedicine synergistic treatments. It also delves into the roles of different immune cell types in promoting anti-tumor immune responses through ferroptosis. Together, these findings provide a comprehensive understanding of synergistic immunotherapy focused on ferroptosis and offer innovative strategies for cancer treatment.

Cucurbitacin B targets STAT3 to induce ferroptosis in non-small cell lung cancer.

Cucurbitacin B (CuB) is a compound found in plants like Cucurbitaceae that has shown promise in fighting cancer, particularly in lung cancer. However, the specific impact of CuB on ferroptosis and how it works in lung cancer cells has not been fully understood. Our research has discovered that CuB can effectively slow down the growth of non-small cell lung cancer (NSCLC) cells. Even in small amounts, it was able to inhibit the growth of various NSCLC cell lines. This inhibitory effect was reversed when ferroptosis inhibitors DFO, Lip-1 and Fer-1 were introduced. CuB was found to increase the levels of reactive oxygen species (ROS), lipid ROS, MDA, and ferrous ions within H358 lung cancer cells, leading to a decrease in GSH, mitochondrial membrane potential (MMP) and changes in ferroptosis-related proteins in a dose-dependent manner. These findings were also confirmed in A549 lung cancer cells. In A549 cells, different concentrations of CuB induced the accumulation of intracellular lipid ROS, ferrous ions and changes in ferroptosis-related indicators in a concentration-dependent manner. Meanwhile, the cytotoxic effect induced by CuB in A549 cells was counteracted by ferroptosis inhibitors DFO and Fer-1. Through network pharmacology, we identified potential targets related to ferroptosis in NSCLC cells treated with CuB, with STAT3 targets showing high scores. Further experiments using molecular docking and cell thermal shift assay (CETSA) revealed that CuB interacts with the STAT3 protein. Western blot and immunofluorescence staining demonstrated that CuB inhibits the phosphorylation of STAT3 (P-STAT3) in H358 cells. Silencing STAT3 enhanced CuB-induced accumulation of lipid ROS and iron ions, as well as the expression of ferroptosis-related proteins. On the other hand, overexpression of STAT3 reversed the effects of CuB-induced ferroptosis. The results indicate that CuB has the capability to suppress STAT3 activation, resulting in ferroptosis, and could be a promising treatment choice for NSCLC.

Ferroptosis-Modulating Natural Products for Targeting Inflammation-Related Diseases: Challenges and Opportunities in Manipulating Redox Signaling.

Significance: Numerous disorders are linked to ferroptosis, a form of programmed cell death triggered by lipid peroxidation accumulation rather than apoptosis. Inflammation is the body's defensive response to stimuli and is also caused by inflammatory chemicals that can harm the body. The treatment of inflammatory diseases by focusing on the signaling pathways and mechanisms of ferroptosis has emerged as a new area worthy of extensive research. Recent Advances: Studies in cellular and animal models of inflammatory diseases have shown that ferroptosis markers are activated and lipid peroxidation levels are increased. Natural products (NPs) are gaining importance due to their ability to target ferroptosis pathways, particularly the Nuclear factor E2-related factor 2 signaling pathway, thereby suppressing inflammation and the release of pro-inflammatory cytokines. Critical Issues: This article provides an overview of ferroptosis, focusing on the signaling pathways and mechanisms connecting it to inflammation. It also explores the potential use of NPs as a treatment for inflammatory diseases and ferroptosis. Future Directions: NPs offer unique advantages, including multicomponent properties, multi-bio-targeting capabilities, and minimal side effects. Further research may facilitate the early clinical application of NPs to develop innovative treatment strategies.

A prognostic framework for predicting lung signet ring cell carcinoma via a machine learning based cox proportional hazard model.

PURPOSE: Signet ring cell carcinoma (SRCC) is a rare type of lung cancer. The conventional survival nomogram used to predict lung cancer performs poorly for SRCC. Therefore, a novel nomogram specifically for studying SRCC is highly required. METHODS: Baseline characteristics of lung signet ring cell carcinoma were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox regression and random forest analysis were performed on the training group data, respectively. Subsequently, we compared results from these two types of analyses. A nomogram model was developed to predict 1-year, 3-year, and 5-year overall survival (OS) for patients, and receiver operating characteristic (ROC) curves and calibration curves were used to assess the prediction accuracy. Decision curve analysis (DCA) was used to assess the clinical applicability of the proposed model. For treatment modalities, Kaplan-Meier curves were adopted to analyze condition-specific effects. RESULTS: We obtained 731 patients diagnosed with lung signet ring cell carcinoma (LSRCC) in the SEER database and randomized the patients into a training group (551) and a validation group (220) with a ratio of 7:3. Eight factors including age, primary site, T, N, and M.Stage, surgery, chemotherapy, and radiation were included in the nomogram analysis. Results suggested that treatment methods (like surgery, chemotherapy, and radiation) and T-Stage factors had significant prognostic effects. The results of ROC curves, calibration curves, and DCA in the training and validation groups demonstrated that the nomogram we constructed could precisely predict survival and prognosis in LSRCC patients. Through deep verification, we found the constructed model had a high C-index, indicating that the model had a strong predictive power. Further, we found that all surgical interventions had good effects on OS and cancer-specific survival (CSS). The survival curves showed a relatively favorable prognosis for T0 patients overall, regardless of the treatment modality. CONCLUSIONS: Our nomogram is demonstrated to be clinically beneficial for the prognosis of LSRCC patients. The surgical intervention was successful regardless of the tumor stage, and the Cox proportional hazard (CPH) model had better performance than the machine learning model in terms of effectiveness.

Feasibility and limitations of combined treatment for lateral pelvic lymph node metastases in rectal cancer.

Colorectal cancer ranks among the most commonly diagnosed cancers globally, and is associated with a high rate of pelvic recurrence after surgery. In efforts to mitigate recurrence, pelvic lymph node dissection (PLND) is commonly advocated as an adjunct to radical surgery. Neoadjuvant chemoradiotherapy (NACRT) is a therapeutic approach employed in managing locally advanced rectal cancer, and has been found to increase the survival rates. Chua et al have proposed a combination of NACRT with selective PLND for addressing lateral pelvic lymph node metastases in rectal cancer patients, with the aim of reducing recurrence and improving survival outcomes. Nevertheless, certain studies have indicated that the addition of PLND to NACRT and total mesorectal excision did not yield a significant reduction in local recurrence rates or improvement in survival. Consequently, meticulous patient selection and perioperative chemotherapy may prove indispensable in ensuring the efficacy of PLND.

TRAF6 Inhibitors from Marine Compound Library: Pharmacophore, Virtual Screening, Fragment Replacement, ADMET, and Molecular Dynamics.

TRAF6 is an E3 ubiquitin ligase that plays a crucial role in cell signaling. It is known that MMP is involved in tumor metastasis, and TRAF6 induces MMP-9 expression by binding to BSG. However, inhibiting TRAF6's ubiquitinase activity without disrupting the RING domain is a challenge that requires further research. To address this, we conducted computer-based drug screening to identify potential TRAF6 inhibitors. Using a ligand-receptor complex pharmacophore based on the inhibitor EGCG, known for its anti-tumor properties, we screened 52,765 marine compounds. After the molecular docking of 405 molecules with TRAF6, six compounds were selected for further analysis. By replacing fragments of non-binding compounds and conducting second docking, we identified two promising molecules, CMNPD9212-16 and CMNPD12791-8, with strong binding activity and favorable pharmacological properties. ADME and toxicity predictions confirmed their potential as TRAF6 inhibitors. Molecular dynamics simulations showed that CMNPD12791-8 maintained a stable structure with the target protein, comparable to EGCG. Therefore, CMNPD12791-8 holds promise as a potential inhibitor of TRAF6 for inhibiting tumor growth and metastasis.

Identification and experimental validation of immune-related gene PPARG is involved in ulcerative colitis.

BACKGROUND: The pathophysiology of ulcerative colitis (UC) is believed to be heavily influenced by immunology, which presents challenges for both diagnosis and treatment. The main aims of this study are to deepen our understanding of the immunological characteristics associated with the disease and to identify valuable biomarkers for diagnosis and treatment. METHODS: The UC datasets were sourced from the GEO database and were analyzed using unsupervised clustering to identify different subtypes of UC. Twelve machine learning algorithms and Deep learning model DNN were developed to identify potential UC biomarkers, with the LIME and SHAP methods used to explain the models' findings. PPI network is used to verify the identified key biomarkers, and then a network connecting super enhancers, transcription factors and genes is constructed. Single-cell sequencing technology was utilized to investigate the role of Peroxisome Proliferator Activated Receptor Gamma (PPARG) in UC and its correlation with macrophage infiltration. Furthermore, alterations in PPARG expression were validated through Western blot (WB) and immunohistochemistry (IHC) in both in vitro and in vivo experiments. RESULT: By utilizing bioinformatics techniques, we were able to pinpoint PPARG as a key biomarker for UC. The expression of PPARG was significantly reduced in cell models, UC animal models, and colitis models induced by dextran sodium sulfate (DSS). Interestingly, overexpression of PPARG was able to restore intestinal barrier function in H2O2-induced IEC-6 cells. Additionally, immune-related differentially expressed genes (DEGs) allowed for efficient classification of UC samples into neutrophil and mitochondrial metabolic subtypes. A diagnostic model incorporating the three disease-specific genes PPARG, PLA2G2A, and IDO1 demonstrated high accuracy in distinguishing between the UC group and the control group. Furthermore, single-cell analysis revealed that decreased PPARG expression in colon tissue may contribute to the polarization of M1 macrophages through activation of inflammatory pathways. CONCLUSION: In conclusion, PPARG, a gene related to immunity, has been established as a reliable potential biomarker for the diagnosis and treatment of UC. The immune response it controls plays a key role in the progression and development of UC by enabling interaction between characteristic biomarkers and immune infiltrating cells.

Mechanisms and potential applications of COPS6 in pan-cancer therapy.

The COP9 signalosome subunit 6 (COPS6) is abnormally overexpressed in many malignancies, yet its precise role in carcinogenesis is unknown. To gain a better understanding of COPS6's role, the authors conducted a pan-cancer analysis using various bioinformatics techniques such as differential expression patterns, prognostic value, gene mutations, immune infiltration, correlation analysis, and functional enrichment assessment. Results showed that COPS6 was highly correlated with prognosis, immune cell infiltration level, tumor mutation burden, and microsatellite instability in patients with a range of tumor types. This suggests that COPS6 may be a potential target for cancer treatment. Overall, this research provides insight into COPS6's role in cancer development and its potential therapeutic applications.

Role of targeting ferroptosis as a component of combination therapy in combating drug resistance in colorectal cancer.

Colorectal cancer (CRC) is a form of cancer that is often resistant to chemotherapy, targeted therapy, radiotherapy, and immunotherapy due to its genomic instability and inflammatory tumor microenvironment. Ferroptosis, a type of non-apoptotic cell death, is characterized by the accumulation of iron and the oxidation of lipids. Studies have revealed that the levels of reactive oxygen species and glutathione in CRC cells are significantly lower than those in healthy colon cells. Erastin has emerged as a promising candidate for CRC treatment by diminishing stemness and chemoresistance. Moreover, the gut, responsible for regulating iron absorption and release, could influence CRC susceptibility through iron metabolism modulation. Investigation into ferroptosis offers new insights into CRC pathogenesis and clinical management, potentially revolutionizing treatment approaches for therapy-resistant cancers.

Honokiol suppress the PD-L1 expression to improve anti-tumor immunity in lung cancer.

Lung cancer is a serious health issue globally, and current treatments have proven to be inadequate. Therefore, immune checkpoint inhibitors (ICIs) that target the PD-1/PD-L1 pathway have become a viable treatment option in lun cancer. Honokiol, a lignan derived from Magnolia officinalis, has been found to possess anti-inflammatory, antioxidant, and antitumor properties. Our research found that honokiol can effectively regulate PD-L1 through network pharmacology and transcriptome analysis. Cell experiments showed that honokiol can significantly reduce PD-L1 expression in cells with high PD-L1 expression. Molecular docking, cellular thermal shift assay (CETSA) and Bio-Layer Interferometry (BLI)indicated that Honokiol can bind to PD-L1. Co-culture experiments on lung cancer cells and T cells demonstrated that honokiol mediates PD-L1 degradation, stimulates T cell activation, and facilitates T cell killing of tumor cells. Moreover, honokiol activates CD4 + and CD8 + T cell infiltration in vivo, thus suppressing tumor growth in C57BL/6 mice. In conclusion, this study has demonstrated that honokiol can inhibit the growth of lung cancer by targeting tumor cell PD-L1, suppressing PD-L1 expression, blocking the PD-1/PD-L1 pathway, and enhancing anti-tumor immunity.