Liver fibrosis is a major cause of death worldwide. As a progressive step in chronic liver disease, fibrosis is almost always diagnosed too late with limited treatment options. Here, we uncover the spatial transcriptional landscape driving human liver fibrosis using single nuclei RNA and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to deconvolute multi-cell spatial transcriptomic profiling in human liver cirrhosis. Through multi-modal data integration, we define molecular signatures driving cell state transitions in liver disease and define an impaired cellular response and directional trajectory between hepatocytes and cholangiocytes associated with disease remodelling. We identify pro-fibrogenic signatures in non-parenchymal cell subpopulations co-localised within the fibrotic niche and localise transitional cell states at the scar interface. This combined approach provides a spatial atlas of gene regulation and defines molecular signatures associated with liver disease for targeted therapeutics or as early diagnostic markers of progressive liver disease.

Protein arginine methyltransferases (PRMTs) are enzymes that catalyze the methylation of arginine residues in eukaryotic proteins, playing critical roles in modulating diverse cellular processes. The importance of PRMTs in the incidence and progression of a wide range of diseases, particularly cancers, such as breast, liver, lung, colorectal cancer, lymphoma, leukemia, and acute myeloid leukemia is increasingly recognized. This underscores the critical need for the development of effective PRMT inhibitors as therapeutic intervention. The field of PRMT inhibitors is in the rapidly growing phase and it is necessary to conduct a summative review of how the so-far developed inhibitors impact PRMT functions and cellular physiology. Our review aims to summarize molecular action mechanisms of these PRMT inhibitors and particularly elaborate their triggered biomedical effects. We describe the cellular phenotype consequences of select PRMT inhibitors across various disease models, thereby providing an understanding of the pharmacological mechanisms underpinning PRMT inhibition. The promising effects of PRMT5 inhibitors in targeted therapy of methylthioadenosine phosphorylase-deleted cancers are particularly highlighted. At last, we provide a perspective on the challenges and further opportunities of developing and applying novel PRMT inhibitors for clinical advancement.

The family of protein arginine methyltransferases (PRMTs) occupies an important position in biology, especially during the initiation and development of cancer. PRMT3 and CARM1(also known as PRMT4), being type I protein arginine methyltransferases, are key in controlling tumour progression by catalysing the mono-methylation and asymmetric di-methylation of both histone and non-histone substrates. This paper reviews the functions and potential therapeutic target value of PRMT3 and CARM1 in a variety of cancers. Studies have identified abnormal expressions of PRMT3 and CARM1 in several malignancies, closely linked to cancer progression, advancement, and resistance to treatment. Such as hepatocellular carcinoma, colorectal cancer, ovarian cancer, and endometrial cancer. These findings offer new strategies and directions for cancer treatment, especially in enhancing the effectiveness of conventional treatment methods.

Astrocyte-microglia crosstalk is vital for neuronal survival and clearing aggregate accumulation in neurodegenerative diseases. While interleukin-3 (IL-3) has been reported to exert both protective and detrimental effects in neurodegenerative diseases, however, its role in α-synuclein pathology remains unclear. In this study, it is found that astrocytic IL-3 and microglial IL-3R are positively responsive to α-synuclein pathology in the brains of transgenic A53T Parkinson's disease (PD) mice and in an adeno-associated virus (AAV)-human α-synuclein (AAV-hα-Syn)-injected PD mouse model. Exogenous IL-3 infusion reduces behavioral abnormities and nigrostriatal α-synuclein pathology. Mechanistically, IL-3 induces microglial phagocytosis of pathological α-synuclein while simultaneously stimulating dopaminergic (DA) neurons to clear pathological α-synuclein via induction of autophagy through the IFN-β/Irgm1 pathway. Due to its limited efficiency in crossing the blood-brain barrier, a precise IL-3 delivery strategy is developed by cross-linking IL-3 and RVG29 with PEG-Linker (RVG-modified IL-3 nanogels-RVG-IL3 NGs). Intravenous administration of RVG-IL3 NGs shows efficient uptake by microglia and DA neurons within the brain. RVG-IL3 NGs ameliorate motor deficits and pathological α-synuclein by improving microglial and neuronal function in the AAV-hα-Syn mouse model of PD. Collectively, IL-3 may represent a feasible therapeutic strategy for PD.

Coactivator-associated arginine methyltransferase 1 (CARM1), pivotal for catalyzing arginine methylation of histone and non-histone proteins, plays a crucial role in developing various cancers. CARM1 was initially recognized as a transcriptional coregulator by orchestrating chromatin remodeling, transcription regulation, mRNA splicing and stability. This diverse functionality contributes to the recruitment of transcription factors that foster malignancies. Going beyond its established involvement in transcriptional control, CARM1-mediated methylation influences a spectrum of biological processes, including the cell cycle, metabolism, autophagy, redox homeostasis, and inflammation. By manipulating these physiological functions, CARM1 becomes essential in critical processes such as tumorigenesis, metastasis, and therapeutic resistance. Consequently, it emerges as a viable target for therapeutic intervention and a possible biomarker for medication response in specific cancer types. This review provides a comprehensive exploration of the various physiological functions of CARM1 in the context of cancer. Furthermore, we discuss potential CARM1-targeting pharmaceutical interventions for cancer therapy.

Coactivator-associated arginine methyltransferase 1 (CARM1) is a protein arginine methyltransferase that deposits asymmetrical dimethylation marks on both histone and nonhistone substrates. The regulatory role of CARM1 in transcription was first identified in estrogen receptor positive (ER+) breast cancer. Since then, the mechanism of CARM1 in activating ER-target genes has been further interrogated. CARM1 is expressed at the highest level in ER negative (ER-) breast cancer and higher expression correlates with poor prognosis, suggesting an oncogenic role of CARM1. Indeed, in ER- breast cancer, CARM1 can promote proliferation and metastasis at least partly through methylation of proteins and activation of oncogenes. In this review, we summarize the mechanisms of transcriptional activation by CARM1 in breast cancer. The methyltransferase activity of CARM1 is important for many of its functions; here, we also highlight the nonenzymatic roles of CARM1. We also cover the biological processes regulated by CARM1 that are often deregulated in cancer and the ways to harness CARM1 in cancer treatment.

Accumulating evidences indicate that the specific alternative splicing (AS) events are linked to the occurrence and prognosis of gastric cancer (GC). Nevertheless, the impact of AS is still unclear and needed to further elucidation.

The expression profile of GC and normal samples were downloaded from TCGA. AS events were achieved from SpliceSeq database. Cox regression together with LASSO analysis were employed to identify survival-associated AS events (SASEs) and calculate risk scores. PPI and pathway enrichment analysis were implemented to determine the function and pathways of these genes. Kaplan-Meier (K-M) analysis and Receiver Operating Characteristic Curves were used to evaluate the clinical significance of genes of SASEs. Q-PCR were applied to validate the hub genes on the survival prognosis in 47 GC samples. Drug sensitivity and immune cell infiltration analysis were conducted.

In total, 48 140 AS events in 10 610 genes from 361 GC and 31 normal samples were analyzed. Through univariate Cox regression, 855 SASEs in 763 genes were screened out. Further, these SASEs were analyzed by PPI and 17 hub genes were identified. Meanwhile, using Lasso and multivariate Cox regression analysis, 135 SASEs in 132 genes related to 7 AS forms were further screened and a GC prognostic model was constructed. K-M curves indicates that high-risk group has poorer prognosis. And the nomogram analysis on the basis of the multivariate Cox analysis was disclosed the interrelationships between 7 AS forms and clinical parameters in the model. Five key genes were then screened out by PPI analysis and Differential Expression Gene analysis based on TCGA and Combined-dataset, namely STAT3, RAD51B, SOCS2, POLE2 and TSR1. The expression levels of AS in STAT3, RAD51B, SOCS2, POLE2 and TSR1 were all significantly correlated with survival by qPCR verification. Nineteen drugs were sensitized to high-risk patients and eight immune cells showed significantly different infiltration between the STAD and normal groups.

In this research, the prognostic model constructed by SASEs can be applied to predict the prognosis of GC patients and the selected key genes are expected to become new biomarkers and therapeutical targets for GC treatment.

Metastasis remains a major challenge in the successful management of malignant diseases. The liver is a major site of metastatic disease and a leading cause of death from gastrointestinal malignancies such as colon, stomach, and pancreatic cancers, as well as melanoma, breast cancer, and sarcoma. As an important factor that influences the development of metastatic liver cancer, alternative splicing drives the diversity of RNA transcripts and protein subtypes, which may provide potential to broaden the target space. In particular, the dysfunction of splicing factors and abnormal expression of splicing variants are associated with the occurrence, progression, aggressiveness, and drug resistance of cancers caused by the selective splicing of specific genes. This review is the first to provide a detailed summary of the normal splicing process and alterations that occur during metastatic liver cancer. It will cover the role of alternative splicing in the mechanisms of metastatic liver cancer by examining splicing factor changes, abnormal splicing, and the contribution of hypoxia to these changes during metastasis.

Gastric cancer (GC) is the fifth most common type of cancer and has the fourth highest death rate among all cancers. There is a lack of studies examining the impact of liver metastases on the effectiveness of immunotherapy in individuals diagnosed with GC.

To investigate the influence of liver metastases on the effectiveness and safety of immunotherapy in patients with advanced GC.

This retrospective investigation collected clinical data of patients with advanced stomach cancer who had immunotherapy at our hospital from February 2021 to January 2023. The baseline attributes were compared using either the Chi-square test or the Fisher exact probability method. The chi-square test and Kaplan-Meier survival analysis were employed to assess the therapeutic efficacy and survival duration in GC patients with and without liver metastases.

The analysis comprised 48 patients diagnosed with advanced GC, who were categorized into two groups: A liver metastasis cohort (n = 20) and a non-liver metastatic cohort (n = 28). Patients with liver metastasis exhibited a more deteriorated physical condition compared to those without liver metastasis. The objective response rates in the cohort with metastasis and the cohort without metastasis were 15.0% and 35.7% (P > 0.05), respectively. Similarly, the disease control rates in these two cohorts were 65.0% and 82.1% (P > 0.05), respectively. The median progression-free survival was 5.0 months in one group and 11.2 months in the other group, with a hazard ratio of 0.40 and a significance level (P) less than 0.05. The median overall survival was 12.0 months in one group and 19.0 months in the other group, with a significance level (P) greater than 0.05.

Immunotherapy is less effective in GC patients with liver metastases compared to those without liver metastasis.

Alternative splicing (AS) serves as a pivotal mechanism in transcriptional regulation, engendering transcript diversity, and modifications in protein structure and functionality. Across varying tissues, developmental stages, or under specific conditions, AS gives rise to distinct splice isoforms. This implies that these isoforms possess unique temporal and spatial roles, thereby associating AS with standard biological activities and diseases. Among these, AS-related RNA-binding proteins (RBPs) play an instrumental role in regulating alternative splicing events. Under physiological conditions, the diversity of proteins mediated by AS influences the structure, function, interaction, and localization of proteins, thereby participating in the differentiation and development of an array of tissues and organs. Under pathological conditions, alterations in AS are linked with various diseases, particularly cancer. These changes can lead to modifications in gene splicing patterns, culminating in changes or loss of protein functionality. For instance, in cancer, abnormalities in AS and RBPs may result in aberrant expression of cancer-associated genes, thereby promoting the onset and progression of tumors. AS and RBPs are also associated with numerous neurodegenerative diseases and autoimmune diseases. Consequently, the study of AS across different tissues holds significant value. This review provides a detailed account of the recent advancements in the study of alternative splicing and AS-related RNA-binding proteins in tissue development and diseases, which aids in deepening the understanding of gene expression complexity and offers new insights and methodologies for precision medicine.

Tumor metastasis severely limits the prognosis of gastric cancer patients. RNA-binding proteins (RBPs) are crucial in tumor metastasis, yet there is limited research into their involvement in gastric cancer. Here, we found that ESRP1, a RBP specific in epithelial cells, is important in regulating the metastasis of gastric cancer cells. ESRP1 is negatively correlated with distant metastasis and lymph node metastasis in gastric cancer patients. And we demonstrated that ESRP1 inhibit migration and invasion of gastric cancer in vitro and in vivo. Mechanistically, ESRP1 promotes exon 11 alternative splicing of CLSTN1 pre-mRNA. The post-splicing short CLSTN1 stabilizes the Ecadherin/β-catenin binding structure, and promotes β-catenin protein ubiquitination and degradation, thereby inhibiting the migration and invasion of gastric cancer cells. Our study highlights the role of ESRP1 in regulating metastasis of gastric cancer and extends its mechanism. These results provide a possibility for ESRP1 and CLSTN1 to become therapeutic targets for metastasis of gastric cancer.

As aberrant alternative splicing by either dysregulation or mutations of splicing factors contributes to cancer initiation and progression, splicing factors are emerging as potential therapeutic targets for cancer therapy. Therefore, pharmacological modulators targeting splicing factors have been under development. Epithelial splicing regulatory protein 1 (ESRP1) is an epithelial cell-specific splicing factor, whose downregulation is associated with epithelial-mesenchymal transition (EMT) by regulating alternative splicing of multiple genes, such as CD44, CTNND1, ENAH, and FGFR2. Consistent with the downregulation of ESRP1 during EMT, it has been initially revealed that high ESRP1 expression is associated with favorable prognosis and ESRP1 plays a tumor-suppressive role in cancer progression. However, ESRP1 has been found to promote cancer progression in some cancers, such as breast and ovarian cancers, indicating that it plays a dual role in cancer progression depending on the type of cancer. Furthermore, recent studies have reported that ESRP1 affects tumor growth by regulating the metabolism of tumor cells or immune cell infiltration in the tumor microenvironment, suggesting the novel roles of ESRP1 in addition to EMT. ESRP1 expression was also associated with response to anticancer drugs. This review describes current understanding of the roles and mechanisms of ESRP1 in cancer progression, and further discusses the emerging novel roles of ESRP1 in cancer and recent attempts to target splicing factors for cancer therapy.

Tissue-specific gene expression generates fundamental differences in the function of each tissue and affects the characteristics of the tumors that are created as a result. However, it is unclear how much the tissue specificity is conserved during grafting of the primary tumor into an immune-compromised mouse model. Here, we performed a comparative RNA-seq analysis of four different primary-patient derived xenograft (PDX) tumors. The analysis revealed a conserved RNA biotype distribution of primary-PDX pairs, as revealed by previous works. Interestingly, we detected significant changes in the splicing pattern of PDX, which was mainly comprised of skipped exons. This was confirmed by splicing variant-specific RT-PCR analysis. On the other hand, the correlation analysis for the tissue-specific genes indicated overall strong positive correlations between the primary and PDX tumor pairs, with the exception of gastric cancer cases, which showed an inverse correlation. These data propose a tissue-specific change in splicing events during PDX formation as a variable factor that affects primary-PDX integrity.

Tumor metastasis is the leading cause of mortality among advanced cancer patients. Understanding its mechanisms and treatment strategies is vital for clinical application. Arginine methylation, a post-translational modification catalyzed by protein arginine methyltransferases (PRMTs), is implicated in diverse physiological processes and disease progressions. Previous research has demonstrated PRMTs' involvement in tumor occurrence, progression, and metastasis. This review offers a comprehensive summary of the relationship between PRMTs, prognosis, and metastasis in various cancers. Our focus centers on elucidating the molecular mechanisms through which PRMTs regulate tumor metastasis. We also discuss relevant clinical trials and effective PRMT inhibitors, including chemical compounds, long non-coding RNA (lncRNA), micro-RNA (miRNA), and nanomaterials, for treating tumor metastasis. While a few studies present conflicting results, the overall trajectory suggests that inhibiting arginine methylation exhibits promise in curtailing tumor metastasis across various cancers. Nonetheless, the underlying mechanisms and molecular interactions are diverse. The development of inhibitors targeting arginine methylation, along with the progression of clinical trials, holds substantial potential in the field of tumor metastasis, meriting sustained attention.

Coactivator-associated arginine methyltransferase 1 (CARM1) is an arginine methyltransferase that posttranslationally modifies proteins that regulate multiple levels of RNA production and processing. Its substrates include histones, transcription factors, coregulators of transcription, and splicing factors. CARM1 is overexpressed in many different cancer types, and often promotes transcription factor programs that are co-opted as drivers of the transformed cell state, a process known as transcription factor addiction. Targeting these oncogenic transcription factor pathways is difficult but could be addressed by removing the activity of the key coactivators on which they rely. CARM1 is ubiquitously expressed, and its KO is less detrimental in embryonic development than deletion of the arginine methyltransferases protein arginine methyltransferase 1 and protein arginine methyltransferase 5, suggesting that therapeutic targeting of CARM1 may be well tolerated. Here, we will summarize the normal in vivo functions of CARM1 that have been gleaned from mouse studies, expand on the transcriptional pathways that are regulated by CARM1, and finally highlight recent studies that have identified oncogenic properties of CARM1 in different biological settings. This review is meant to kindle an interest in the development of human drug therapies targeting CARM1, as there are currently no CARM1 inhibitors available for use in clinical trials.

KIAA1324 is a transmembrane protein largely reported as a tumor suppressor and favorable prognosis marker in various cancers, including gastric cancer. In this study, we report the role of N-linked glycosylation in KIAA1324 as a functional post-translational modification (PTM). Loss of N-linked glycosylation eliminated the potential of KIAA1324 to suppress cancer cell proliferation and migration. Furthermore, we demonstrated that KIAA1324 undergoes fucosylation, a modification of the N-glycan mediated by fucosyltransferase, and inhibition of fucosylation also significantly suppressed KIAA1324-induced cell growth inhibition and apoptosis of gastric cancer cells. In addition, KIAA1324-mediated apoptosis and tumor regression were inhibited by the loss of N-linked glycosylation. RNA sequencing (RNAseq) analysis revealed that genes most relevant to the apoptosis and cell cycle arrest pathways were modulated by KIAA1324 with the N-linked glycosylation, and Gene Regulatory Network (GRN) analysis suggested novel targets of KIAA1324 for anti-tumor effects in the transcription level. The N-linked glycosylation blockade decreased protein stability through rapid proteasomal degradation. The non-glycosylated mutant also showed altered localization and lost apoptotic activity that inhibits the interaction between GRP78 and caspase 7. These data demonstrate that N-linked glycosylation of KIAA1324 is essential for the suppressive role of KIAA1324 protein in gastric cancer progression and indicates that KIAA1324 may have anti-tumor effects by targeting cancer-related genes with N-linked glycosylation. In conclusion, our study suggests the PTM of KIAA1324 including N-linked glycosylation and fucosylation is a necessary factor to consider for cancer prognosis and therapy improvement.

Gastric cancer is an aggressive disease with increasing global incidence in recent years. Human epidermal growth receptor 2 (HER2) is overexpressed in approximately 10-20% of gastric cancers. The implementation of targeted therapy against HER2 as part of the standard of care treatment in metastatic disease has improved the prognosis of this subset of patients. However, gastric cancer still has high mortality rates and urgently requires new treatment strategies. The combination of immunotherapy with HER2-targeted therapies has shown synergistic effects in preclinical models, this being the rationale behind exploring this combination in clinical trials in locally advanced and metastatic settings. Additionally, the irruption of antibody-drug conjugates and other novel HER2-targeted agents has led to the development of numerous clinical trials showing promising results. This review presents the molecular mechanisms supporting the use of HER2-targeted drugs in combination with immunotherapy and provides an overview of the therapeutic scenario of HER2-positive disease. We focus on the role of immunotherapy but also summarize emerging therapies and combinations under clinical research that may change the standard treatment in HER-2 positive disease in the future.

Coactivator-associated arginine methyltransferase 1 (CARM1), a type I protein arginine methyltransferase (PRMT), has been widely reported to catalyze arginine methylation of histone and non-histone substrates, which is closely associated with the occurrence and progression of cancer. Recently, accumulating studies have demonstrated the oncogenic role of CARM1 in many types of human cancers. More importantly, CARM1 has been emerging as an attractive therapeutic target for discovery of new candidate anti-tumor drugs. Therefore, in this review, we summarize the molecular structure of CARM1 and its key regulatory pathways, as well as further discuss the rapid progress in better understanding of the oncogenic functions of CARM1. Moreover, we further demonstrate several representative targeted CARM1 inhibitors, especially focusing on demonstrating their designing strategies and potential therapeutic applications. Together, these inspiring findings would shed new light on elucidating the underlying mechanisms of CARM1 and provide a clue on discovery of more potent and selective CARM1 inhibitors for the future targeted cancer therapy.