Colorectal liver metastases grow following different histologic growth patterns (HGPs), classified as desmoplastic and nondesmoplastic (dHGP, non-dHGP), being the latter associated with worst prognosis. This study aimed to investigate the tumor microenvironment (TME) between HGPs supporting different survival. Multiplexed immunohistochemical staining was performed with the Opal7 system in a 100-patients cohort to evaluate the tumor–liver interface with three different cell panels: lymphoid, myeloid, and carcinoma-associated fibroblasts. Differences between HGPs were assessed by Mann–Whitney U test with Pratt correction and Holm–Bonferroni multitest adjustment. Cytotoxic T-cells were more abundant in tumoral areas of dHGP, while non-dHGP had higher macrophages infiltration, Th2, CD163⁺, and Calprotectin⁺ cells as well as higher pSMAD2 expression. Regarding carcinoma-associated fibroblasts, several subsets expressing COL1A1 were enriched in dHGP, while αSMA^low_single cells were present at higher densities in non-dHGP. Interestingly, Calprotectin⁺ cells confer better prognoses in non-dHGP, identifying a subgroup of good outcome patients that unexpectedly also show an enrichment in other myeloid cells. In summary, our results illustrate different TME landscapes with respect to HGPs. dHGP presents a higher degree of immunocompetence, higher amounts of Collagen 1 as well as lesser presence of myeloid cell populations, features that might be influencing on the better prognosis of encapsulated metastases.

Heart degenerative diseases pose a significant challenge due to the limited ability of native heart to restore lost cardiomyocytes. Direct cellular reprogramming technology, particularly the use of small molecules, has emerged as a promising solution to prepare functional cardiomyocyte through faster and safer processes without genetic modification. However, current methods of direct reprogramming often exhibit low conversion efficiencies and immature characteristics of the generated cardiomyocytes, limiting their use in regenerative medicine. This study proposes the use of mitochondrial delivery to metabolically reprogram chemically induced cardiomyocyte-like cells (CiCMs), fostering enhanced maturity and functionality. Our findings show that mitochondria sourced from high-energy-demand organs (liver, brain, and heart) can enhance structural maturation and metabolic functions. Notably, heart-derived mitochondria resulted in CiCMs with a higher oxygen consumption rate capacity, enhanced electrical functionality, and higher sensitivity to hypoxic condition. These results are related to metabolic changes caused by increased number and size of mitochondria and activated mitochondrial fusion after mitochondrial treatment. In conclusion, our study suggests that mitochondrial delivery into CiCMs can be an effective strategy to promote cellular maturation, potentially contributing to the advancement of regenerative medicine and disease modeling.

Colitis, accompanied by the accumulation of reactive oxygen species (ROS) in the intestinal tract, is a risk factor for colorectal cancer (CRC). Our previous studies indicate that nicotinamide mononucleotide (NMN) replenishment reduces chronic inflammation. In this study, we confirm that NMN supplementation reduces inflammatory cytokine levels and oxidative tissue damage in an azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-associated cancer (CAC) model. Mice treated with NMN developed fewer colon tumors than untreated animals under the same AOM/DSS treatment conditions. Quantitative proteomic analysis revealed a decrease in signal transducer and activator of transcription 1 (STAT1) expression in the CAC model. We demonstrate that STAT1 overexpression induces G1 arrest by downregulating CDK6 expression and suppressing tumor cell proliferation and migration. Of note, H₂O₂ induced trioxidation of the STAT1 protein and promoted its degradation, which was partially reversed by NMN supplementation. Upon H₂O₂ treatment, Cys155 in STAT1 was oxidized to sulfonic acid, whereas the mutation of Cys155 to alanine abolished ROS-mediated STAT1 degradation. These results indicate that oxidative stress induces STAT1 degradation in tumor cells and possibly in CAC tissues, whereas supplementation with NMN protects STAT1 from oxidation-induced degradation and prevents tumorigenesis. This study provides experimental evidence for the development of NMN-mediated chemoprevention strategies for CRC.

Research on virus/receptor interactions has uncovered various mechanisms of antibody-mediated neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, understanding of neutralization by antibodies targeting the silent face, which recognize epitopes on glycan shields, remains limited, and their potential protective efficacy in vivo is not well understood. This study describes a silent face neutralizing antibody, 3711, which targets a non-supersite on the N-terminal domain (NTD) of the spike protein. Cryo-EM structure determination of the 3711 Fab in the spike complex reveals a novel neutralizing epitope shielded by glycans on the spike’s silent face. Antibody 3711 inhibits the interaction between the receptor-binding domain (RBD) and human angiotensin-converting enzyme 2 (hACE2) through steric hindrance and exhibits superior in vivo protective effects compared to other reported NTD-targeted monoclonal antibodies (mAbs). Competition assays and antibody repertoire analysis indicate the rarity of antibodies targeting the 3711-related epitope in SARS-CoV-2 convalescents, suggesting the infrequency of NTD silent face-targeted neutralizing antibodies during SARS-CoV-2 infection. As the first NTD silent face-targeted neutralizing antibody against SARS-CoV-2, the identification of mAb 3711, with its novel neutralizing mechanism, enhances our understanding of neutralizing epitopes on glycan shields and elucidates epitope-guided viral mutations that evade specific antibodies.

Extracellular vesicles (EVs) composed of various biologically active constituents, such as proteins, nucleic acids, lipids, and metabolites, have emerged as a noteworthy mode of intercellular communication. There are several categories of EVs, including exosomes, microvesicles, and apoptotic bodies, which largely differ in their mechanisms of formation and secretion. The amount of evidence indicated that changes in the EV quantity and composition play a role in multiple aspects of cancer development, such as the transfer of oncogenic signals, angiogenesis, metabolism remodeling, and immunosuppressive effects. As EV isolation technology and characteristics recognition improve, EVs are becoming more commonly used in the early diagnosis and evaluation of treatment effectiveness for cancers. Actually, EVs have sparked clinical interest in their potential use as delivery vehicles or vaccines for innovative antitumor techniques. This review will focus on the function of biological molecules contained in EVs linked to cancer progression and their participation in the intricate interrelationship within the tumor microenvironment. Furthermore, the potential efficacy of an EV-based liquid biopsy and delivery cargo for treatment will be explored. Finally, we explicitly delineate the limitations of EV-based anticancer therapies and provide an overview of the clinical trials aimed at improving EV development.

Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent lipid peroxidation in membrane phospholipids. Since its identification in 2012, extensive research has unveiled its involvement in the pathophysiology of numerous diseases, including cancers, neurodegenerative disorders, organ injuries, infectious diseases, autoimmune conditions, metabolic disorders, and skin diseases. Oxidizable lipids, overload iron, and compromised antioxidant systems are known as critical prerequisites for driving overwhelming lipid peroxidation, ultimately leading to plasma membrane rupture and ferroptotic cell death. However, the precise regulatory networks governing ferroptosis and ferroptosis-targeted therapy in these diseases remain largely undefined, hindering the development of pharmacological agonists and antagonists. In this review, we first elucidate core mechanisms of ferroptosis and summarize its epigenetic modifications (e.g., histone modifications, DNA methylation, noncoding RNAs, and N6-methyladenosine modification) and nonepigenetic modifications (e.g., genetic mutations, transcriptional regulation, and posttranslational modifications). We then discuss the association between ferroptosis and disease pathogenesis and explore therapeutic approaches for targeting ferroptosis. We also introduce potential clinical monitoring strategies for ferroptosis. Finally, we put forward several unresolved issues in which progress is needed to better understand ferroptosis. We hope this review will offer promise for the clinical application of ferroptosis-targeted therapies in the context of human health and disease.

Colorectal adenomas (CRAs) represent precancerous lesions that precede the development of colorectal cancer (CRC). Regular monitoring of CRAs can hinder the progression into carcinoma. To explore the utility of tissue DNA and circulating cell-free DNA (cfDNA) in early diagnosis of CRC, we retrospectively sequenced paired tissue and plasma samples from 85 patients with conventional CRAs. The genetic alterations identified were compared with those from 78 stage-I CRC patients (CRC-I) in the ChangKang project. Within the CRA cohort, we pinpointed 12 genes, notably APC, KRAS, and SOX9, that exhibited significant mutated rates in tissue. Patients harboring KMT2C and KMT2D mutations displayed persistent polyps. By comparing with the mutational profiles of metastatic CRC plasma samples, we found that ZNF717 was exclusively mutated in CRAs, while KMT2C and KMT2D mutations were detected in both CRA and CRC. The presence of cfDNA mutations in plasma was validated through polymerase chain reaction, enhancing the feasibility of using cfDNA mutations for early CRC screening. Compared with CRC-I, CRAs exhibited a reduced frequency of TP53 and PIK3CA somatic mutations and underwent non-neutral evolution more often. We established a random forest model based on 15 characteristic genes to distinguish CRA and CRC, achieving an area under the curve of 0.89. Through this endeavor, we identified two novel genes, CNTNAP5 and GATA6, implicated in CRC carcinogenesis. Overall, our findings reveal convincing biomarkers markers for detecting CRAs with a propensity for CRC development, highlighting the importance of early genetic screening in CRC prevention.

The gut microbiota plays a critical role in maintaining human health, influencing a wide range of physiological processes, including immune regulation, metabolism, and neurological function. Recent studies have shown that imbalances in gut microbiota composition can contribute to the onset and progression of various diseases, such as metabolic disorders (e.g., obesity and diabetes) and neurodegenerative conditions (e.g., Alzheimer’s and Parkinson’s). These conditions are often accompanied by chronic inflammation and dysregulated immune responses, which are closely linked to specific forms of cell death, including pyroptosis and ferroptosis. Pathogenic bacteria in the gut can trigger these cell death pathways through toxin release, while probiotics have been found to mitigate these effects by modulating immune responses. Despite these insights, the precise mechanisms through which the gut microbiota influences these diseases remain insufficiently understood. This review consolidates recent findings on the impact of gut microbiota in these immune-mediated and inflammation-associated conditions. It also identifies gaps in current research and explores the potential of advanced technologies, such as organ-on-chip models and the microbiome–gut–organ axis, for deepening our understanding. Emerging tools, including single-bacterium omics and spatial metabolomics, are discussed for their promise in elucidating the microbiota’s role in disease development.

The blood–brain barrier is often altered in glioblastoma (GBM) creating a blood–brain–tumor barrier (BBTB) composed of pericytes. The BBTB affects chemotherapy efficacy. However, the expression signatures of BBTB-associated pericytes remain unclear. We aimed to identify BBTB-associated pericytes in single-cell RNA sequencing data of GBM using pericyte markers, a normal brain pericyte expression signature, and functional enrichment. We identified parathyroid hormone receptor-1 (PTH1R) as a potential marker of pericytes associated with BBTB function. These pericytes interact with other cells in GBM mainly through extracellular matrix–integrin signaling pathways. Compared with normal pericytes, pericytes in GBM exhibited upregulation of several ECM genes (including collagen IV and FN1), and high expression levels of these genes were associated with a poor prognosis. Cell line experiments showed that PTH1R knockdown in pericytes increased collagen IV and FN1 expression levels. In mice models, the expression levels of PTH1R, collagen IV, and FN1 were consistent with these trends. Evans Blue leakage and IgG detection in the brain tissue suggested a negative correlation between PTH1R expression levels and blood–brain barrier function. Further, a risk model based on differentially expressed genes in PTH1R⁺ pericytes had predictive value for GBM, as validated using independent and in-house cohorts.

Respiratory syncytial virus (RSV) is a predominant pathogen responsible for respiratory tract infections among infants, the elderly, and immunocompromised individuals. In recent years, significant progress has been made in innovative vaccines and therapeutic agents targeting RSV. Nevertheless, numerous challenges and bottlenecks persist in the prevention and treatment of RSV infections. This review will provide an overview of the resolved and unresolved issues surrounding the development of vaccines and therapeutic agents against RSV. As of September 2024, three RSV vaccines against acute lower respiratory infections (ALRI) have been approved globally. Additionally, there have been notable progress in the realm of passive immunoprophylactic antibodies, with the monoclonal antibody nirsevimab receiving regulatory approval for the prevention of RSV infections in infants. Furthermore, a variety of RSV therapeutic agents are currently under clinical investigation, with the potential to yield breakthrough advancements in the foreseeable future. This review delineates the advancements and challenges faced in vaccines and therapeutic agents targeting RSV. It aims to provide insights that will guide the development of effective preventive and control measures for RSV.

Increasing evidences indicate that the gut microbiota is involved in the development and therapy of gastrointestinal and hepatic disease. Imbalance of gut microbiota occurs in the early stages of diseases, and maintaining the balance of the gut microbiota provides a new strategy for the treatment of diseases. It has been reported that Parabacteroides distasonis is associated with multiple diseases. As the next-generation probiotics, several studies have demonstrated its positive regulation on the gastrointestinal and hepatic disease, including inflammatory bowel disease, colorectal cancer, hepatic fibrosis, and fatty liver. The function of P. distasonis and its metabolites mainly affect host immune system, intestinal barrier function, and metabolic networks. Manipulation of P. distasonis with natural components lead to the protective effect on enterohepatic disease. In this review, the metabolic pathways regulated by P. distasonis are summarized to illustrate its active metabolites and their impact on host metabolism, the role and action mechanism in gastrointestinal and hepatic disease are discussed. More importantly, the natural components can be used to manipulate P. distasonis as treatment strategies, and the challenges and perspectives of P. distasonis in clinical applications are discussed.

Lung cancer (LC) continues to pose the highest mortality and exhibits a common prevalence among all types of cancer. The genetic interaction between human eukaryotes and microbial cells plays a vital role in orchestrating every physiological activity of the host. The dynamic crosstalk between gut and lung microbiomes and the gut–lung axis communication network has been widely accepted as promising factors influencing LC progression. The advent of the 16s rDNA sequencing technique has opened new horizons for elucidating the lung microbiome and its potential pathophysiological role in LC and other infectious lung diseases using a molecular approach. Numerous studies have reported the direct involvement of the host microbiome in lung tumorigenesis processes and their impact on current treatment strategies such as radiotherapy, chemotherapy, or immunotherapy. The genetic and metabolomic cross-interaction, microbiome-dependent host immune modulation, and the close association between microbiota composition and treatment outcomes strongly suggest that designing microbiome-based treatment strategies and investigating new molecules targeting the common holobiome could offer potential alternatives to develop effective therapeutic principles for LC treatment. This review aims to highlight the interaction between the host and microbiome in LC progression and the possibility of manipulating altered microbiome ecology as therapeutic targets.

Exosomes can regulate the malignant progression of tumors by carrying a variety of genetic information and transmitting it to target cells. Recent studies indicate that exosomal circular RNAs (circRNAs) regulate multiple biological processes in carcinogenesis, such as tumor growth, metastasis, epithelial–mesenchymal transition, drug resistance, autophagy, metabolism, angiogenesis, and immune escape. In the tumor microenvironment (TME), exosomal circRNAs can be transferred among tumor cells, endothelial cells, cancer-associated fibroblasts, immune cells, and microbiota, affecting tumor initiation and progression. Due to the high stability and widespread presence of exosomal circRNAs, they hold promise as biomarkers for tumor diagnosis and prognosis prediction in blood and urine. In addition, designing nanoparticles targeting exosomal circRNAs and utilizing exosomal circRNAs derived from immune cells or stem cells provide new strategies for cancer therapy. In this review, we examined the crucial role of exosomal circRNAs in regulating tumor-related signaling pathways and summarized the transmission of exosomal circRNAs between various types of cells and their impact on the TME. Finally, our review highlights the potential of exosomal circRNAs as diagnostic and prognostic prediction biomarkers, as well as suggesting new strategies for clinical therapy.

Ocular immune-related diseases, represent a spectrum of conditions driven by immune system dysregulation, include but not limit to uveitis, diabetic retinopathy, age-related macular degeneration, Graves’ ophthalmopathy, etc. The molecular and cellular mechanisms underlying these diseases are typically dysfunctioned immune responses targeting ocular tissues, resulting in inflammation and tissue damage. Recent advances have further elucidated the pivotal role of different immune responses in the development, progression, as well as management of various ocular immune diseases. However, there is currently a relative lack of connection between the cellular mechanisms and treatments of several immune-related ocular diseases. In this review, we discuss recent findings related to the immunopathogenesis of above-mentioned diseases. In particular, we summarize the different types of immune cells, inflammatory mediators, and associated signaling pathways that are involved in the pathophysiology of above-mentioned ophthalmopathies. Furthermore, we also discuss the future directions of utilizing anti-inflammatory regime in the management of these diseases. This will facilitate a better understanding of the pathogenesis of immune-related ocular diseases and provide new insights for future treatment approaches.

Breast cancer is the leading cancer among women, with a significant number experiencing recurrence and metastasis, thereby reducing survival rates. This study focuses on the role of long noncoding RNAs (lncRNAs) in breast cancer immunotherapy response. We conducted an analysis involving 1027 patients from Sun Yat-sen Memorial Hospital, Sun Yat-sen University, and The Cancer Genome Atlas, utilizing RNA sequencing and pathology whole-slide images. We employed unsupervised clustering to identify distinct lncRNA expression patterns and developed an AI-based pathology model using convolutional neural networks to predict immune–metabolic subtypes. Additionally, we created a multimodal model integrating lncRNA data, immune-cell scores, clinical information, and pathology images for prognostic prediction. Our findings revealed four unique immune–metabolic subtypes, and the AI model demonstrated high predictive accuracy, highlighting the significant impact of lncRNAs on antitumor immunity and metabolic states within the tumor microenvironment. The AI-based pathology model, DeepClinMed-IM, exhibited high accuracy in predicting these subtypes. Additionally, the multimodal model, DeepClinMed-PGM, integrating pathology images, lncRNA data, immune-cell scores, and clinical information, showed superior prognostic performance. In conclusion, these AI models provide a robust foundation for precise prognostication and the identification of potential candidates for immunotherapy, advancing breast cancer research and treatment strategies.

Programmed cell death represents a precisely regulated and active cellular demise, governed by a complex network of specific genes and proteins. The identification of multiple forms of programmed cell death has significantly advanced the understanding of its intricate mechanisms, as demonstrated in recent studies. A thorough grasp of these processes is essential across various biological disciplines and in the study of diseases. Nonetheless, despite notable progress, the exploration of the relationship between programmed cell death and disease, as well as its clinical application, are still in a nascent stage. Therefore, further exploration of programmed cell death and the development of corresponding therapeutic methods and strategies holds substantial potential. Our review provides a detailed examination of the primary mechanisms behind apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis. Following this, the discussion delves into biological functions and diseases associated dysregulated programmed cell death. Finally, we highlight existing and potential therapeutic targets and strategies focused on cancers and neurodegenerative diseases. This review aims to summarize the latest insights on programmed cell death from mechanisms to diseases and provides a more reliable approach for clinical transformation.

Numerous organisms in nature have demonstrated enhanced biocompatibility, precise tumor targeting capabilities, and efficient tissue traversal within the human body. Drawing inspiration from these organisms, researchers have employed bioengineering, bioconjugation, and micro- or nanotechnology to fabricate bioinspired micro- and nanostructured systems. These systems play a crucial role in addressing the limitations of conventional anticancer drugs and nanomaterials concerning biocompatibility, effective penetration of physiological barriers, as well as selective tumor targeting, thereby leading to improved therapeutic efficacy while minimizing nonspecific adverse effects on healthy cells. Consequently, extensive exploration of these bioinspired micro- and nanostructured systems has been undertaken across various cancer treatment modalities with some progressing into preclinical or clinical stages. However, our understanding of this field remains limited which may impede research progress, clinical translation efforts, and practical applications. Therefore, this study presents a systematic classification of bioinspired micro- and nanostructured systems for cancer therapy that comprehensively elucidates their sources of inspiration and design principles. Furthermore, it extensively discusses the current status of clinical translation efforts while identifying prevailing challenges and exploring future prospects. This work will establish a robust theoretical framework and serve as a valuable reference to facilitate advancements in research and clinical application within this field.

RNA modification has emerged as a crucial area of research in epigenetics, significantly influencing tumor biology by regulating RNA metabolism. N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification, the sole known acetylation in eukaryotic RNA, influences cancer pathogenesis and progression. NAT10 is the only writer of ac4C and catalyzes acetyl transfer on targeted RNA, and ac4C helps to improve the stability and translational efficiency of ac4C-modified RNA. NAT10 is highly expressed and associated with poor prognosis in pan-cancers. Based on its molecular mechanism and biological functions, ac4C is a central factor in tumorigenesis, tumor progression, drug resistance, and tumor immune escape. Despite the increasing focus on ac4C, the specific regulatory mechanisms of ac4C in cancer remain elusive. The present review thoroughly analyzes the current knowledge on NAT10-mediated ac4C modification in cancer, highlighting its broad regulatory influence on targeted gene expression and tumor biology. This review also summarizes the limitations and perspectives of current research on NAT10 and ac4C in cancer, to identify new therapeutic targets and advance cancer treatment strategies.

Cerebral vascular malformations (CVMs), particularly cerebral cavernous malformations and cerebral arteriovenous malformations, pose significant neurological challenges due to their complex etiologies and clinical implications. Traditionally viewed as congenital conditions with structural abnormalities, CVMs have been treated primarily through resection, embolization, and stereotactic radiosurgery. While these approaches offer some efficacy, they often pose risks to neurological integrity due to their invasive nature. Advances in next-generation sequencing, particularly high-depth whole-exome sequencing and bioinformatics, have facilitated the identification of gene variants from neurosurgically resected CVMs samples. These advancements have deepened our understanding of CVM pathogenesis. Somatic mutations in key mechanistic pathways have been identified as causative factors, leading to a paradigm shift in CVM treatment. Additionally, recent progress in noninvasive and minimally invasive techniques, including gene imaging genomics, liquid biopsy, or endovascular biopsies (endovascular sampling of blood vessel lumens), has enabled the identification of gene variants associated with CVMs. These methods, in conjunction with clinical data, offer potential for early detection, dynamic monitoring, and targeted therapies that could be used as monotherapy or adjuncts to surgery. This review highlights advancements in CVM pathogenesis and precision therapies, outlining the future potential of precision medicine in CVM management.

The skin serves as the first protective barrier for nonspecific immunity and encompasses a vast network of skin-associated immune cells. Atopic dermatitis (AD) is a prevalent inflammatory skin disease that affects individuals of all ages and races, with a complex pathogenesis intricately linked to genetic, environmental factors, skin barrier dysfunction as well as immune dysfunction. Individuals diagnosed with AD frequently exhibit genetic predispositions, characterized by mutations that impact the structural integrity of the skin barrier. This barrier dysfunction leads to the release of alarmins, activating the type 2 immune pathway and recruiting various immune cells to the skin, where they coordinate cutaneous immune responses. In this review, we summarize experimental models of AD and provide an overview of its pathogenesis and the therapeutic interventions. We focus on elucidating the intricate interplay between the immune system of the skin and the complex regulatory mechanisms, as well as commonly used treatments for AD, aiming to systematically understand the cellular and molecular crosstalk in AD-affected skin. Our overarching objective is to provide novel insights and inform potential clinical interventions to reduce the incidence and impact of AD.

Ovarian cancer (OV) ranks among the deadliest gynecological cancer, known for its high risk of relapse and metastasis, and a general resistance to conventional platinum-based chemotherapy. Selenoprotein I (SELENOI) is a crucial mediator implicated in human hereditary spastic paraplegia. However, its role in human tumors remains poorly elucidated. Here, we comprehensively analyzed SELENOI expression patterns, functions, and clinical implications across various malignancies through the integration of bulk transcriptomics, cancer databases, and in vitro and in vivo experiments. Pan-cancer analysis indicated upregulated SELENOI expression across various cancers, correlating with augmented malignancy, suppressed tumor immunity and poor prognosis. Knockdown of SELENOI caused G0/G1-phase cell cycle arrest and diminished aggressive cancer phenotypes in OV cells. Moreover, SELENOI inhibition augments ferroptosis and reverses the cisplatin resistance in OV cells by modulating Akt phosphorylation. Conversely, overexpression of SELENOI in OV cells enhanced therapeutic sensitivity to cisplatin by upregulating Akt phosphorylation. Importantly, in vivo studies demonstrated that SELENOI inhibition suppressed ovarian tumor growth and enhanced cisplatin’s anticancer effects. These findings highlight the significant role of SELENOI in OV by modulating ferroptosis and chemotherapy resistance. Targeting SELENOI represents a promising therapeutic approach to promote the efficacy of platinum-based chemotherapy in OV, particularly in cases of resistance.

Deubiquitinating enzymes (DUBs) regulate substrate ubiquitination by removing ubiquitin or cleaving within ubiquitin chains, thereby maintaining cellular homeostasis. Approximately 100 DUBs in humans counteract E3 ubiquitin ligases, finely balancing ubiquitination and deubiquitination processes to maintain cellular proteostasis and respond to various stimuli and stresses. Given their role in modulating ubiquitination levels of various substrates, DUBs are increasingly linked to human health and disease. Here, we review the DUB family, highlighting their distinctive structural characteristics and chain-type specificities. We show that DUB family members regulate key signaling pathways, such as NF-κB, PI3K/Akt/mTOR, and MAPK, and play crucial roles in tumorigenesis and other diseases (neurodegenerative disorders, cardiovascular diseases, inflammatory disorders, and developmental diseases), making them promising therapeutic targets Our review also discusses the challenges in developing DUB inhibitors and underscores the critical role of the DUBs in cellular signaling and cancer. This comprehensive analysis enhances our understanding of the complex biological functions of the DUBs and underscores their therapeutic potential.