Antioxidative, Anti-Inflammatory, Antibacterial, Photo-Cross-Linkable Hydrogel of Gallic Acid-Chitosan Methacrylate: Synthesis, In Vitro, and In Vivo Assessments.

Chitosan (CS)-based photo-cross-linkable hydrogels have gained increasing attention in biomedical applications. In this study, we grafted CS with gallic acid (GA) by carbodiimide chemistry to prepare the GA-CS conjugate, which was subsequently modified with methacrylic anhydride (MA) modification to obtain the methacrylated GA-CS conjugate (GA-CS-MA). Our results demonstrated that the GA-CS-MA hydrogel not only exhibited improved physicochemical properties but also showed antibacterial, antioxidative, and anti-inflammatory capacity. It showed moderate antibacterial activity and especially showed a more powerful inhibitory effect against Gram-positive bacteria. It modulated macrophage polarization, downregulated pro-inflammatory gene expression, upregulated anti-inflammatory gene expression, and significantly reduced reactive oxygen species (ROS) and nitric oxide (NO) production under lipopolysaccharide (LPS) stimulation. Subcutaneously implanted GA-CS-MA hydrogels induced significantly lower inflammatory responses, as evidenced by less inflammatory cell infiltration, thinner fibrous capsule, and predominately promoted M2 polarization. This study provides a feasible strategy to prepare CS-based photo-cross-linkable hydrogels with improved physicochemical properties for biomedical applications.

Non-coding RNA in exosomes: Regulating bone metastasis of lung cancer and its clinical application prospect.

Lung cancer is a highly prevalent malignancy with poor prognosis and rapid progression. It most frequently metastasizes to the bone, where it can pose a severe threat to the patient's survival. Once metastasized, the disease is often incurable and can result in severe complications such as hypercalcemia, bone pain, fractures, spinal cord compression, and subsequent paralysis. Exosomes are bilayer vesicle nanoparticles secreted by most of the extracellular vesicles, which can be found in almost all organisms and play an essential role in intercellular communication. Through their ability to regulate related bone cells, exosomes carry bioactive molecules, including proteins, lipids, and non-coding RNAs (ncRNAs), that can be extremely important in bone remodeling. Studies have been conducted on the role play by proteins, lncRNA, and microRNA-all ncRNAs-carried by exosomes in the bone metastases of lung cancer. In this review, the latest progress of the regulatory mechanism of ncRNAs carried by exosomes in lung cancer bone metastasis has been reviewed. The clinical use of exosomes as a promising biomarker, drug transporter, and therapeutic target was highlighted to offer a novel diagnostic and treatment approach for patients with lung cancer bone metastases.

Nrf-2 as a novel target in radiation induced lung injury.

Radiation-induced lung injury (RILI) is a common and fatal complication of chest radiotherapy. The underlying mechanisms include radiation-induced oxidative stress caused by damage to the deoxyribonucleic acid (DNA) and production of reactive oxygen species (ROS), resulting in apoptosis of lung and endothelial cells and recruitment of inflammatory cells and myofibroblasts expressing NADPH oxidase to the site of injury, which in turn contribute to oxidative stress and cytokine production. Nuclear factor erythroid 2-related factor 2 (Nrf-2) is a vital transcription factor that regulates oxidative stress and inhibits inflammation. Studies have shown that Nrf-2 protects against radiation-induced lung inflammation and fibrosis. This review discusses the protective role of Nrf-2 in RILI and its possible mechanisms.

Krüpple-like factors in cardiomyopathy: emerging player and therapeutic opportunities.

Cardiomyopathy, a heterogeneous pathological condition characterized by changes in cardiac structure or function, represents a significant risk factor for the prevalence and mortality of cardiovascular disease (CVD). Research conducted over the years has led to the modification of definition and classification of cardiomyopathy. Herein, we reviewed seven of the most common types of cardiomyopathies, including Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), diabetic cardiomyopathy, Dilated Cardiomyopathy (DCM), desmin-associated cardiomyopathy, Hypertrophic Cardiomyopathy (HCM), Ischemic Cardiomyopathy (ICM), and obesity cardiomyopathy, focusing on their definitions, epidemiology, and influencing factors. Cardiomyopathies manifest in various ways ranging from microscopic alterations in cardiomyocytes, to tissue hypoperfusion, cardiac failure, and arrhythmias caused by electrical conduction abnormalities. As pleiotropic Transcription Factors (TFs), the Krüppel-Like Factors (KLFs), a family of zinc finger proteins, are involved in regulating the setting and development of cardiomyopathies, and play critical roles in associated biological processes, including Oxidative Stress (OS), inflammatory reactions, myocardial hypertrophy and fibrosis, and cellular autophagy and apoptosis, particularly in diabetic cardiomyopathy. However, research into KLFs in cardiomyopathy is still in its early stages, and the pathophysiologic mechanisms of some KLF members in various types of cardiomyopathies remain unclear. This article reviews the roles and recent research advances in KLFs, specifically those targeting and regulating several cardiomyopathy-associated processes.

Anti-inflammatory and anti-oxidative electrospun nanofiber membrane promotes diabetic wound healing via macrophage modulation.

BACKGROUND: In the inflammatory milieu of diabetic chronic wounds, macrophages undergo substantial metabolic reprogramming and play a pivotal role in orchestrating immune responses. Itaconic acid, primarily synthesized by inflammatory macrophages as a byproduct in the tricarboxylic acid cycle, has recently gained increasing attention as an immunomodulator. This study aims to assess the immunomodulatory capacity of an itaconic acid derivative, 4-Octyl itaconate (OI), which was covalently conjugated to electrospun nanofibers and investigated through in vitro studies and a full-thickness wound model of diabetic mice. RESULTS: OI was feasibly conjugated onto chitosan (CS), which was then grafted to electrospun polycaprolactone/gelatin (PG) nanofibers to obtain P/G-CS-OI membranes. The P/G-CS-OI membrane exhibited good mechanical strength, compliance, and biocompatibility. In addition, the sustained OI release endowed the nanofiber membrane with great antioxidative and anti-inflammatory activities as revealed in in vitro and in vivo studies. Specifically, the P/G-CS-OI membrane activated nuclear factor-erythroid-2-related factor 2 (NRF2) by alkylating Kelch-like ECH-associated protein 1 (KEAP1). This antioxidative response modulates macrophage polarization, leading to mitigated inflammatory responses, enhanced angiogenesis, and recovered re-epithelization, finally contributing to improved healing of mouse diabetic wounds. CONCLUSIONS: The P/G-CS-OI nanofiber membrane shows good capacity in macrophage modulation and might be promising for diabetic chronic wound treatment.

Synovial microenvironment-influenced mast cells promote the progression of rheumatoid arthritis.

Mast cells are phenotypically and functionally heterogeneous, and their state is possibly controlled by local microenvironment. Therefore, specific analyses are needed to understand whether mast cells function as powerful participants or dispensable bystanders in specific diseases. Here, we show that degranulation of mast cells in inflammatory synovial tissues of patients with rheumatoid arthritis (RA) is induced via MAS-related G protein-coupled receptor X2 (MRGPRX2), and the expression of MHC class II and costimulatory molecules on mast cells are upregulated. Collagen-induced arthritis mice treated with a combination of anti-IL-17A and cromolyn sodium, a mast cell membrane stabilizer, show significantly reduced clinical severity and decreased bone erosion. The findings of the present study suggest that synovial microenvironment-influenced mast cells contribute to disease progression and may provide a further mast cell-targeting therapy for RA.

The Radioprotective Effect of LBP on Neurogenesis and Cognition after Acute Radiation Exposure.

BACKGROUND: Radiation exposure has been linked to the development of brain damage and cognitive impairment, but the protective effect and mechanism of Lycium barbarum pills (LBP) on radiation-induced neurological damage remains to be clarified. METHODS: Behavioral tests and immunohistochemical studies were conducted to evaluate the protective effects of LBP extract (10 g/kg orally daily for 4 weeks) against radiation-induced damage on neurogenesis and cognitive function in Balb/c mice exposed to 5.5 Gy X-ray acute radiation. RESULTS: The results showed that the LBP extract significantly improved body weight loss, locomotor activity and spatial learning and memory. Immunohistochemical tests revealed that the LBP extract prevented the loss of proliferating cells, newly generated neurons and interneurons, especially in the subgranular area of the dentate gyrus. CONCLUSION: The findings suggest that LBP is a potential neuroprotective drug for mitigating radiation-induced neuropsychological disorders.

The Role and Application of the AMPK-Sirtuins Network in Cellular Senescence.

Aging and related diseases significantly affect the health and happiness index around the world. Cellular senescence is the basis of physiological aging and is closely related to various senile diseases. AMP-activated protein kinase (AMPK) is associated with both the regulation of cellular energy metabolism and the regulation of cellular senescence. Another set of proteins, sirtuins, has also been demonstrated to play an important role in cell senescence. However, it is not clear how AMPK and sirtuins coordinate to regulate cellular senescence. Herein, we summarized the role of AMPK and sirtuins in regulating metabolism, repairing DNA damage, and even prolonging human life. We have provided a detailed explanation of the clinical trials relating to the AMPK and sirtuins involved in aging. Systematically analyzing individual senescence genes and developing functional reference notes will aid in understanding the potential mechanisms underlying aging and identify therapeutic targets for both anti-aging interventions and age-related illnesses.

Chemokines: Function and therapeutic potential in bone metastasis of lung cancer.

Lung cancer is a rapidly progressing disease with a poor prognosis. Bone metastasis is commonly found in 40.6% of advanced-stage patients. The mortality rate of lung cancer patients with bone metastasis can be significantly decreased by implementing novel diagnostic techniques, improved staging and classification systems, precise surgical interventions, and advanced treatment modalities. However, it is important to note that there is currently a lack of radical procedures available for these patients due to the development of drug resistance. Consequently, palliative care approaches are commonly employed in clinical practice. Therefore, new understandings of the process of bone metastasis of lung cancer are critical for developing better treatment strategies to improve patient's clinical cure rate and quality of life. Chemokines are cell-secreted small signaling proteins in cancer occurrence, proliferation, invasion, and metastasis. In this study, we review the development of bone metastasis in lung cancer and discuss the mechanisms of specific chemokine families (CC, CXC, CX3C, and XC) in regulating the biological activities of tumors and promoting bone metastasis. We also highlight some preclinical studies and clinical trials on chemokines for lung cancer and bone metastasis.

RNA nanotechnology: A new chapter in targeted therapy.

Nanoparticles have been widely studied in the fields of biotechnology, pharmacy, optics and medicine and have broad application prospects. Numerous studies have shown significant interest in utilizing nanoparticles for chemically coating or coupling drugs, aiming to address the challenges of drug delivery, including degradability and uncertainty. Furthermore, the utilization of lipid nanoparticles loaded with novel coronavirus antigen mRNA to control the COVID-19 pandemic has led to a notable surge in research on nanoparticle vaccines. Hence, nanoparticles have emerged as a crucial delivery system for disease prevention and treatment, bearing immense significance. Current research highlights that nanoparticles offer superior efficacy and potential compared to conventional drug treatment and prevention methods. Notably, for drug delivery applications, it is imperative to utilize biodegradable nanoparticles. This paper reviews the structures and characteristics of various biodegradable nanoparticles and their applications in biomedicine in order to inspire more researchers to further explore the functions of nanoparticles. RNA plays a pivotal role in regulating the occurrence and progression of diseases, but its inherent susceptibility to degradation poses a challenge. In light of this, we conducted a comprehensive review of the research advancements concerning RNA-containing biodegradable nanoparticles in the realm of disease prevention and treatment, focusing on cancer, inflammatory diseases, and viral infections.

Recent Progress in the Development and Clinical Application of New Drugs for Transthyretin Cardiac Amyloidosis.

ABSTRACT: Transthyretincardiac amyloidosis is a rare disease that has gained significant attention in recent years because of misfolding of transthyretin fibrils produced by the liver, leading to their deposition in the myocardium. The disease has an insidious onset, nonspecific clinical manifestations, and historically lacked effective drugs, making early diagnosis and treatment challenging. The survival time of patients largely depends on the extent of heart involvement at the time of diagnosis, and conventional treatments for cardiovascular disease do not provide significant benefits. Effective management of the disease requires treatment of its underlying cause. Orthotopic liver transplantation and combined hepato-heart transplantation have been clinically effective means of treating transthyretin cardiac amyloidosis mutants for many years. However, transplantation has many limitations in clinical practice. In recent years, the development of new drugs has brought new hope to patients. This review presents the latest advances in drug development and clinical application to provide a reference for clinicians managing transthyretin cardiac amyloidosis.

Advances in the treatment of pancreatic cancer with traditional Chinese medicine.

Pancreatic cancer is a common malignancy of the digestive system. With a high degree of malignancy and poor prognosis, it is called the "king of cancers." Currently, Western medicine treats pancreatic cancer mainly by surgical resection, radiotherapy, and chemotherapy. However, the curative effect is not satisfactory. The application of Traditional Chinese Medicine (TCM) in the treatment of pancreatic cancer has many advantages and is becoming an important facet of comprehensive clinical treatment. In this paper, we review current therapeutic approaches for pancreatic cancer. We also review the protective effects shown by TCM in different models and discuss the potential molecular mechanisms of these.

TERT Mutations in Non-Small Cell Lung Cancer: Clinicopathologic Features and Prognostic Implications.

Introduction: The associations between the clinical characteristics of non-small cell lung cancer (NSCLC) and mutations in telomerase reverse transcriptase (TERT) gene remain unclear. In this study, we used next-generation sequencing (NGS) to investigate the incidence rate and clinical correlates of TERT mutations in patients with NSCLC. Methods: In total, 283 tumor samples from patients with NSCLC were tested using an NGS panel from September 2017 to May 2020. The genetic testing results and clinical data of all patients were collected. Results: TERT mutations were found in 30 patients, which were significantly associated with age, smoking history, sex, and metastasis (P < 0.05). Survival analyses showed that patients who carried TERT mutations had a poorer prognosis. Of the 30 TERT-mutation carriers, 17 harbored epidermal growth factor receptor (EGFR) mutations, which were significantly associated with sex, histopathology type, and metastasis (P < 0.05; overall survival [OS], 21 months; 95% confidence interval [CI], 8.153-33.847 months). Three TERT mutation patients harbored Kirsten rat sarcoma virus (KRAS) mutations, which were significantly associated with metastasis risk (P < 0.05), KRAS mutations carriers had a worse prognosis, with an OS of 10 months (95% CI, 8.153-33.847 months). Multivariate Cox regression analyses showed that age, cancer stage, and TERT mutation carrier status were independent risk factors for NSCLC, and the TERT mutation was 2.731 times higher than that without TERT mutation (95% CI, 1.689-4.418, P < 0.001). Conclusions: TERT mutations were present in 11% of patients with NSCLC. TERT mutations were associated with age, smoking history, sex, and distant metastasis. Co-mutations in TERT and EGFR/KRAS indicated a poor prognosis. The co-mutations of TERT and EGFR differed according to sex, histopathology type, and metastasis, whereas TERT and KRAS co-mutations were only associated with patient metastasis. Age, cancer stage, and TERT mutation carrier status were independent risk factors for poor prognosis in patients with NSCLC.

Ependyma in Neurodegenerative Diseases, Radiation-Induced Brain Injury and as a Therapeutic Target for Neurotrophic Factors.

The neuron loss caused by the progressive damage to the nervous system is proposed to be the main pathogenesis of neurodegenerative diseases. Ependyma is a layer of ciliated ependymal cells that participates in the formation of the brain-cerebrospinal fluid barrier (BCB). It functions to promotes the circulation of cerebrospinal fluid (CSF) and the material exchange between CSF and brain interstitial fluid. Radiation-induced brain injury (RIBI) shows obvious impairments of the blood-brain barrier (BBB). In the neuroinflammatory processes after acute brain injury, a large amount of complement proteins and infiltrated immune cells are circulated in the CSF to resist brain damage and promote substance exchange through the BCB. However, as the protective barrier lining the brain ventricles, the ependyma is extremely vulnerable to cytotoxic and cytolytic immune responses. When the ependyma is damaged, the integrity of BCB is destroyed, and the CSF flow and material exchange is affected, leading to brain microenvironment imbalance, which plays a vital role in the pathogenesis of neurodegenerative diseases. Epidermal growth factor (EGF) and other neurotrophic factors promote the differentiation and maturation of ependymal cells to maintain the integrity of the ependyma and the activity of ependymal cilia, and may have therapeutic potential in restoring the homeostasis of the brain microenvironment after RIBI or during the pathogenesis of neurodegenerative diseases.

Nanoparticles advanced from preclinical studies to clinical trials for lung cancer therapy.

Lung cancer is the leading cause of cancer mortality. As a heterogeneous disease, it has different subtypes and various treatment modalities. In addition to conventional surgery, radiotherapy and chemotherapy, targeted therapy and immunotherapy have also been applied in the clinics. However, drug resistance and systemic toxicity still cannot be avoided. Based on the unique properties of nanoparticles, it provides a new idea for lung cancer therapy, especially for targeted immunotherapy. When nanoparticles are used as carriers of drugs with special physical properties, the nanodrug delivery system ensures the accuracy of targeting and the stability of drugs while increasing the permeability and the aggregation of drugs in tumor tissues, showing good anti-tumor effects. This review introduces the properties of various nanoparticles including polymer nanoparticles, liposome nanoparticles, quantum dots, dendrimers, and gold nanoparticles and their applications in tumor tissues. In addition, the specific application of nanoparticle-based drug delivery for lung cancer therapy in preclinical studies and clinical trials is discussed.

CX-4945 inhibits fibroblast-like synoviocytes functions through the CK2-p53 axis to reduce rheumatoid arthritis disease severity.

Fibroblast-like synoviocytes (FLS) mediate many pathological processes in rheumatoid arthritis (RA), including pannus formation, bone erosion, and inflammation. RA FLS have unique aggressive phenotypes and exhibit several tumor cell-like characteristics, including hyperproliferation, excessive migration and invasion. Casein kinase 2 (CK2) is reportedly overexpressed in numerous tumor types, and targeted inhibition of CK2 has therapeutic benefits for tumors. However, the expression level of CK2 and its functions in RA FLS remain unclear. Herein, we aimed to elucidate whether CK2 is responsible for the aggressive phenotypes of RA FLS and whether targeted therapy can alleviate the severity of RA. We found that CK2 subunits were elevated in RA FLS compared with osteoarthritis FLS, and the activity of CK2 also markedly increased in RA FLS. Targeted inhibition of CK2 using CX-4945 suppressed RA FLS proliferation through cell cycle arrest. Cell migration and invasion were also inhibited by CX-4945 treatment. Moreover, CX-4945 reduced Interleukin-6 (IL-6), CC motif chemokine ligand 2 (CCL2) and Matrix metalloproteinase-3 (MMP-3) secretion in RA FLS. Further proteomic investigation revealed that p53 signaling pathway significantly changes after CX-4945 treatment in RA FLS. The siRNA-mediated p53 knockdown partly abolished the anti-proliferation and reduced IL-6, MMP-3 secretion effects of CX-4945. Furthermore, CX-4945 administration alleviates arthritis severity in CIA mice. Collectively, our results demonstrated the abnormal elevation of CK2 and its positive association with abnormal phenotypes in RA FLS. Our novel findings suggest the possible therapeutic potential of CX-4945 for RA.

LncRNAs has been identified as regulators of Myeloid-derived suppressor cells in lung cancer.

Lung tumours are widespread pathological conditions that attract much attention due to their high incidence of death. The immune system contributes to the progression of these diseases, especially non-small cell lung cancer, resulting in the fast evolution of immune-targeted therapy. Myeloid-derived suppressor cells (MDSCs) have been suggested to promote the progression of cancer in the lungs by suppressing the immune response through various mechanisms. Herein, we summarized the clinical studies on lung cancer related to MDSCs. However, it is noteworthy to mention the discovery of long non-coding RNAs (lncRNAs) that had different phenotypes and could regulate MDSCs in lung cancer. Therefore, by reviewing the different phenotypes of lncRNAs and their regulation on MDSCs, we summarized the lncRNAs' impact on the progression of lung tumours. Data highlight LncRNAs as anti-cancer agents. Hence, we aim to discuss their possibilities to inhibit tumour growth and trigger the development of immunosuppressive factors such as MDSCs in lung cancer through the regulation of lncRNAs. The ultimate purpose is to propose novel and efficient therapy methods for curing patients with lung tumours.

Deep learning algorithm reveals two prognostic subtypes in patients with gliomas.

BACKGROUND: Gliomas are highly complex and heterogeneous tumors, rendering prognosis prediction challenging. The advent of deep learning algorithms and the accessibility of multi-omic data represent a new approach for the identification of survival-sensitive subtypes. Herein, an autoencoder-based approach was used to identify two survival-sensitive subtypes using RNA sequencing (RNA-seq) and DNA methylation (DNAm) data from The Cancer Genome Atlas (TCGA) dataset. The subtypes were used as labels to build a support vector machine model with cross-validation. We validated the robustness of the model on Chinese Glioma Genome Atlas (CGGA) dataset. DNAm-driven genes were identified by integrating DNAm and gene expression profiling analyses using the R MethylMix package and carried out for further enrichment analysis. RESULTS: For TCGA dataset, the model produced a high C-index (0.92 ± 0.02), low brier score (0.16 ± 0.02), and significant log-rank p value (p < 0.0001). The model also had a decent performance for CGGA dataset (CGGA DNAm: C-index of 0.70, brier score of 0.21; CGGA RNA-seq: C-index of 0.79, brier score of 0.18). Moreover, we identified 389 DNAm-driven genes of survival-sensitive subtypes, which were significantly enriched in the glutathione metabolism pathway. CONCLUSIONS: Our study identified two survival-sensitive subtypes of glioma and provided insights into the molecular mechanisms underlying glioma development; thus, potentially providing a new target for the prognostic prediction of gliomas and supporting personalized treatment strategies.

Prognostic role of multiple abnormal genes in non-small-cell lung cancer.

BACKGROUND: Non-small-cell lung cancer (NSCLC) has the highest morbidity and mortality rates among all malignant tumor types. Although therapies targeting the mutated genes such as KRAS have been used in the clinic for many years, the prognosis remains poor. Therefore, it is necessary to further study the aberrant expression or mutation of non-target genes affecting the survival and prognosis. AIM: To explore the impact of simultaneous abnormalities of multiple genes on the prognosis and survival of patients. METHODS: We used R packages to analyze gene expression data and clinical data downloaded from The Cancer Genome Atlas (TCGA) database. We also collected samples from 85 NSCLC patients from the First People's Hospital of Jingzhou City and retrospectively followed the patients. Multivariate Cox regression analysis and survival analysis were performed. RESULTS: Analysis of gene expression data from TCGA revealed that the overexpression of the following single genes affected overall survival: TP53 (P = 0.79), PTEN (P = 0.94), RB1 (P = 0.49), CTNNB1 (P = 0.24), STK11 (P = 0.32), and PIK3CA (P = 0.013). However, the probability of multiple genes (TP53, PTEN, RB1, and STK11) affecting survival was 0.025. Retrospective analysis of clinical data revealed that sex (hazard ratio [HR] = 1.29; [95%CI: 0.64-2.62]), age (HR = 1.05; [95%CI: 1.02-1.07]), smoking status (HR = 2.26; [95%CI: 1.16-4.39]), tumor histology (HR = 0.58; [95%CI: 0.30-1.11]), cancer stage (HR = 16.63; [95%CI: 4.8-57.63]), epidermal growth factor receptor (EGFR) mutation (HR = 1.82; [95%CI: 1.05-3.16]), abundance (HR = 4.95; [95%CI: 0.78-31.36]), and treatment with tyrosine kinase inhibitors (TKIs) (HR = 0.58; [95%CI: 0.43-0.78]) affected patient survival. Co-occurring mutations of TP53, PTEN, RB1, and STK11 did not significantly affect the overall survival of patients receiving chemotherapy (P = 0.96) but significantly affected the overall survival of patients receiving TKIs (P = 0.045). CONCLUSION: Co-occurring mutation or overexpression of different genes has different effects on the overall survival and prognosis of NSCLC patients. Combined with TKI treatment, the co-occurring mutation of some genes may have a synergistic effect on the survival and prognosis of NSCLC patients.

ROS1-positive non-small cell lung cancer (NSCLC): biology, diagnostics, therapeutics and resistance.

ROS1 is a proto-oncogene encoding a receptor tyrosine protein kinase (RTK), homologous to the v - Ros sequence of University of Manchester tumours virus 2 (UR2) sarcoma virus, whose ligands are still being investigated. ROS1 fusion genes have been identified in various types of tumours. As an oncoprotein, it promotes cell proliferation, activation and cell cycle progression by activating downstream signalling pathways, accelerating the development and progression of non-small cell lung cancer (NSCLC). Studies have demonstrated that ROS1 inhibitors are effective in patients with ROS1-positive NSCLC and are used for first-line clinical treatment. These small molecule inhibitors provide a rational therapeutic option for the treatment of ROS1-positive patients. Inevitably, ROS1 inhibitor resistance mutations occur, leading to tumours recurrence or progression. Here, we comprehensively review the identified biological properties and Differential subcellular localisation of ROS1 fusion oncoprotein promotes tumours progression. We summarise recently completed and ongoing clinical trials of the classic and new ROS1 inhibitors. More importantly, we classify the complex evolving tumours cell resistance mechanisms. This review contributes to our understanding of the biological properties of ROS1 and current therapeutic advances and resistant tumours cells, and the future directions to develop ROS1 inhibitors with durable effects.