Targeting deubiquitinating enzymes in cancer: navigating context-dependence for precision medicine

BackgroundColorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with the tumor microenvironment (TME) playing a pivotal role in its progression and therapeutic resistance. The ubiquitin–proteasome system (UPS), a central regulator of intracellular protein degradation, is increasingly recognized for its involvement in cancer pathogenesis, though its specific role in modulating the CRC TME remains to be fully elucidated. This review aims to systematically summarize current evidence on how the UPS influences the immunosuppressive network within the CRC TME and to evaluate its potential as a therapeutic target.MethodsWe conducted a comprehensive literature search in PubMed, Web of Science, and Scopus databases for original research articles and reviews published between January 2010 and August 2025, using keywords including “ubiquitin–proteasome system,” “colorectal cancer,” “tumor microenvironment,”“immune escape,”and “targeted therapy.” Studies were selected based on their relevance to UPS-mediated regulatory mechanisms in CRC TME remodeling, immune cell function, and treatment response.ResultsOur analysis of preclinical and clinical evidence reveals that the UPS critically regulates immune evasion in CRC through multiple mechanisms: (1) USP14 stabilizes indoleamine 2,3-dioxygenase 1 (IDO1), enhancing tryptophan catabolism and kynurenine accumulation, which suppresses T-cell activity; (2) E3 ligases including SPOP, C-Cbl, KLHL22, and FBW7 modulate PD-L1/PD-1 protein stability via ubiquitination, thereby influencing immune checkpoint signaling; and (3) ZFP91 facilitates K63-linked ubiquitination of PP2Ac, impairing mTORC1-mediated glycolysis in T cells and reinforcing regulatory T-cell immunosuppression. Additionally, the UPS intersects with key oncogenic pathways such as Wnt/β-catenin, NF-κB, and p53, further shaping the immunosuppressive landscape of CRC.ConclusionsTargeting the UPS represents a promising strategy to reverse immunosuppression and overcome therapy resistance in CRC. The primary advantage of this approach lies in its ability to simultaneously disrupt multiple immunosuppressive pathways within the TME, offering a potential solution to the limitations of single-target therapies. Current approaches include proteasome inhibitors, E3 ligase modulators, and deubiquitinating enzyme inhibitors, with combination regimens—such as UPS inhibitors with immune checkpoint blockade—showing synergistic efficacy in preclinical models. Future efforts should focus on enhancing the selectivity of UPS-targeting agents, minimizing off-target effects, and integrating genomic profiling to guide personalized treatment. While current evidence strongly supports the therapeutic potential of UPS targeting, its establishment as a reliable alternative therapy in the clinic will depend on overcoming these challenges and validating efficacy in human trials. This review underscores the UPS as a central regulator of the CRC TME and provides a rational basis for novel therapeutic development.

Despite advances in small-molecule inhibitors (SMIs), the clinical outcomes for glioblastoma (GBM) remain bleak. Recently, polymerase I and transcript release factor (PTRF/Cavin1) has emerged as a promising therapeutic target, with its inhibitor EPIC-1042 demonstrating preclinical anti-tumor activity. However, the therapeutic limitations of SMIs necessitate alternative strategies to achieve enduring target suppression. EPIC-0726, a proteolysis-targeting chimera (PROTAC) degrader of PTRF, was developed through computer-aided drug design (CADD). Target engagement and degradation specificity were validated by Western blot. Quantitative proteomics identified downstream effectors, while mechanistic insights were elucidated through co-immunoprecipitation, immunofluorescence, and ubiquitination profiling. Orthotopic GBM models were used to assess therapeutic efficacy and temozolomide (TMZ) sensitization. EPIC-0726 induced dose-dependent PTRF degradation via the ubiquitin-proteasome system (UPS), requiring ternary complex formation. Proteomic analysis revealed RBX1, a core component of E3 ligase complexes, as a key downstream target. PTRF degradation by EPIC-0726 destabilized RBX1, concurrently suppressing K63-linked ubiquitination-mediated ERK1/2/AKT activation and stabilizing p21 via impaired K48-dependent proteasomal degradation. In vivo, EPIC-0726 monotherapy inhibited GBM growth and synergized with TMZ, with effects more potent than that of EPIC-1042. This study establishes PROTAC-mediated PTRF degradation as a mechanistically distinct manner to activate proteolysis strategy-enhanced temozolomide efficacy by ERK1/2/AKT kinase suppression and p21 stabilization (PEAKS) through the PTRF-RBX1 regulatory axis. The superior efficacy of EPIC-0726 over EPIC-1042, particularly in overcoming TMZ resistance, provides a paradigm-shifting therapeutic approach for GBM. Our findings warrant the clinical translation of EPIC-0726 as both a monotherapy and a backbone for combination regimens.

ABSTRACTIntroduction: Ubiquitin-proteasome system (UPS) has been validated as a novel anticancer drug target in the past 20 years. The UPS contains two distinct steps: ubiquitination of a substrate protein by ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3), and substrate degradation by the 26S proteasome complex. The E3 enzyme is the central player in the ubiquitination step and has a wide range of specific substrates in cancer cells, offering great opportunities for discovery and development of selective drugs.Areas covered: This review summarizes the recent advances in small molecule inhibitors of E1s, E2s, and E3s, with a focus on the latest patents (from 2015 to 2018) of E3 inhibitors and modulators.Expert opinion: One strategy to overcome limitations of current 20S proteasome inhibitors is to discover inhibitors of the upstream key components of the UPS, such as E3 enzymes. E3s play important roles in cancer development and determine the specificity of substrate ubiquitination, offering novel target opportunities. E3 modulators could be developed by rational design, natural compound or library screening, old drug repurposes, and application of other novel technologies. Further understanding of mechanisms of E3–substrate interaction will be essential for discovering and developing next-generation E3 inhibitors as effective anticancer drugs.

Osteoarthritis refers to a degenerative disease with joint pain as the main symptom, and it is caused by various factors, including fibrosis, chapping, ulcers, and loss of articular cartilage. Traditional treatments can only delay the progression of osteoarthritis, and patients may need joint replacement eventually. As a class of organic compound molecules weighing less than 1000 daltons, small molecule inhibitors can target proteins as the main components of most drugs clinically. Small molecule inhibitors for osteoarthritis are under constant research. In this regard, by reviewing relevant manuscripts, small molecule inhibitors targeting MMPs, ADAMTS, IL-1, TNF, WNT, NF-κB, and other proteins were reviewed. We summarized these small molecule inhibitors with different targets and discussed disease-modifying osteoarthritis drugs based on them. These small molecule inhibitors have good inhibitory effects on osteoarthritis, and this review will provide a reference for the treatment of osteoarthritis.

Background Ulcerative colitis (UC) is a chronic inflammatory bowel disease posing a growing global health burden. Current therapies face safety concerns and fail to induce mucosal healing. Mesenchymal stem cell (MSC) therapy has emerged as a promising alternative due to its immunomodulatory and regenerative properties. However, its integration into precision medicine paradigms remains challenging. Methods This review examines the key challenges hindering the clinical translation of MSC therapy for UC and proposes innovative strategies to optimize this cell‐based modality. The analysis is based on a systematic evaluation of the current literature, encompassing the biological properties of MSCs, preclinical studies, clinical trial data, biomanufacturing processes, and emerging technological platforms. Results Our analysis identifies key barriers to precision MSC therapy across biomanufacturing, clinical translation, and mechanistic understanding. To address these challenges, we propose a strategic framework that progresses from challenge identification to developing biological strategies for enhancing MSC potency and homing, streamlining therapeutic workflows, and integrating intelligent systems. Conclusion As a viable therapy for UC, MSC therapy faces significant challenges within the precision medicine paradigm. The convergence of novel approaches with artificial intelligence (AI) is paving the way for precision frameworks, and their rigorous validation through clinical trials will be crucial to delivering reliable, patient‐specific therapies. Highlights Overviews key challenges and innovative strategies in MSC therapy for UC within a precision medicine framework. Examines barriers in MSC biomanufacturing, clinical translation, and host microenvironment adaptation. Highlights emerging approaches, encompassing pharmacological preconditioning, 3D culture, cellular engineering, and advanced delivery platforms to enhance MSC potency and homing. Proposes an integrated roadmap combining standardized workflows, combinatorial regimens, and AI for predictive patient stratification and individualized therapy.

Current treatments for localized prostate cancer include brachytherapy, external beam radiation, surgery, and active surveillance. Unfortunately, 20-40% of prostate cancer patients will experience recurrence and require hormonal therapies. These therapies involve androgen ablation by chemical or surgical castration and application of antiandrogens. Hormonal therapy is initially effective, but will inevitably fail and the disease will progress to lethal castration-resistant prostate cancer (CRPC) from which patients succumb within 2years. CRPC is considered to be dependent on transcriptionally active androgen receptors (AR). This article reviews recent advances in the discovery and development of small molecule inhibitors of AR. A PubMed database search was performed for articles focused on small molecule inhibitors of AR for potential development for the treatment of prostate cancer. Compounds with broad effects on other pathways were not included. Currently, there are several novel antiandrogens being tested in the clinic that have improved affinity for the AR and work by different mechanisms to the current battery of approved antiandrogens that are discussed. Small molecule inhibitors that interact with regions other than the AR ligand-binding pocket have been also been discovered. These small molecules include allosteric inhibitors of the LBD, compounds that alter AR conformation, and antagonists to the AR NTD and are highlighted. CRPC is dependent upon transcriptionally active AR. Survival improvement may be achieved by complete blockade of all AR activity using novel small molecule inhibitors with unique mechanisms of action.

ABSTRACTNon‐small cell lung cancer (NSCLC) remains a leading cause of cancer mortality. Despite advancements in gene targeted therapies and immunotherapies, high heterogeneity contributes to limited efficacy and therapeutic resistance. Ubiquitination, a crucial post‐translational modification that regulates protein stability and degradation, plays a significant role in cancer pathogenesis by influencing key oncogenic pathways and tumour progression. This review systematically explores the ubiquitin‐proteasome system (UPS) and its potential as a therapeutic target for NSCLC. We highlight recent preclinical and clinical studies focusing on ubiquitination‐related biomarkers, drug targets and emerging therapies like proteasome inhibitors and Proteolysis‐targeting chimeras (PROTACs). By exploring the impact of the UPS on tumour biology, the progression of NSCLC and its response to therapy, we aim to underscore the potential of targeting the ubiquitination‐deubiquitination system as a complementary or synergistic approach to existing therapeutic strategies in NSCLC, thereby enhancing patient outcomes and overcoming treatment resistance.

Precision Medicine (PM) is an emerging approach that appears with the impression of changing the existing paradigm of medical practice. Recent advances in technological innovations and genetics, and the growing availability of health data have set a new pace of the research and imposes a set of new requirements on different stakeholders. To date, some studies are available that discuss about different aspects of PM. Nevertheless, a holistic representation of those aspects deemed to confer the technological perspective, in relation to applications and challenges, is mostly ignored. In this context, this paper surveys advances in PM from informatics viewpoint and reviews the enabling tools and techniques in a categorized manner. In addition, the study discusses how other technological paradigms including big data, artificial intelligence, and internet of things can be exploited to advance the potentials of PM. Furthermore, the paper provides some guidelines for future research for seamless implementation and wide-scale deployment of PM based on identified open issues and associated challenges. To this end, the paper proposes an integrated holistic framework for PM motivating informatics researchers to design their relevant research works in an appropriate context.

Cancer remains one of the most challenging diseases to treat, demanding innovative approaches to combat its complexity and heterogeneity. In recent years, Pyridoxal kinase (PDXK), a critical enzyme in the vitamin B6 metabolic pathway, has emerged as a promising target in the pursuit of effective cancer therapies. PDXK, responsible for phosphorylating vitamin B6 to its active forms, plays a pivotal role in various cellular processes, including DNA synthesis, amino acid metabolism, and immune regulation. Dysregulation of PDXK expression has been implicated in cancer, contributing to tumorigenesis and progression. Recent advances in small molecule inhibitors and activators targeting PDXK have showcased their potential to alter cancer cell behavior. These molecules hold promise not only as standalone treatments but also as adjuvants to conventional therapies, augmenting their efficacy. Moreover, PDXK modulation has a profound impact on tumor metabolism. By perturbing vitamin B6 homeostasis, it disrupts the bioenergetics and redox balance within cancer cells, rendering them vulnerable to therapeutic intervention. Combining PDXK modulation with existing cancer therapies, such as chemotherapy or immunotherapy, offers the tantalizing prospect of synergistic treatment approaches, potentially enhancing therapeutic outcomes while minimizing side effects. This review explores the therapeutic potential of PDXK modulation as a novel strategy in the battle against cancer.

KRAS mutations drive approximately 25% of human cancers, with KRAS G12D being the most prevalent and challenging to target. Recent advances have led to developing small molecule inhibitors that selectively target the active GTP-bound state of KRAS G12D, blocking downstream signaling and oncogenic activity. These compounds show strong therapeutic potential.

Targeting hematopoietic progenitor kinase 1 (HPK1) for tumor immunotherapy: advances in small molecule inhibitors.

Caspases are a family of intracellular cysteine proteases that play critical roles in both cytokine maturation and apoptosis. Since this family of enzymes was discovered, there has been increasing interest in their pharmacological modulation, which may provide useful therapies for inflammatory diseases, such as rheumatoid arthritis, or in conditions where inappropriate apoptosis contributes to disease pathologies such as neurodegenerative disorders and ischaemia-related cell death. Thus, there is currently considerable activity in the search for caspase inhibitors. This review describes and summarises selected patent activity in this field from January 1998 to April 2001, with particular emphasis placed on those patents which disclose novel small molecule inhibitors of this important class of enzymes.

Review on advances in small molecule inhibitors on the treatment of inflammatory bowel disease.

Protein phosphatases are primarily responsible for dephosphorylation modification within signal transduction pathways. Phosphatase of regenerating liver-3 (PRL-3) is a dual-specific phosphatase implicated in cancer pathogenesis. Understanding PRL-3's intricate functions and developing targeted therapies is crucial for advancing cancer treatment. This review highlights its regulatory mechanisms, expression patterns, and multifaceted roles in cancer progression. PRL-3's involvement in proliferation, migration, invasion, metastasis, angiogenesis, and drug resistance is discussed. Regulatory mechanisms encompass transcriptional control, alternative splicing, and post-translational modifications. PRL-3 exhibits selective expressions in specific cancer types, making it a potential target for therapy. Despite advances in small molecule inhibitors, further research is needed for clinical application. PRL-3-zumab, a humanized antibody, shows promise in preclinical studies and clinical trials. Our review summarizes the current understanding of the cancer-related cellular function of PRL-3, its prognostic value, and the research progress of therapeutic inhibitors.

This narrative analysis research investigates the use of artificial intelligence (AI) in precision medicine. It focuses specifically on how AI technology may be used to improve precision medical practice and patient outcomes. The combination of artificial intelligence (AI) with precision medicine has the potential to revolutionize health care. Precision medicine is a type of healthcare that considers an individual's genetic, environmental, and behavioural characteristics. The resource-based view (RBV) theoretical framework is used in this study to give a lens through which to explore the many components required in incorporating AI for precision medicine. These components include AI technology, resource acquisition, resource utilization, resource heterogeneity, and resource complementarity. This study attempts to provide light on the possible benefits, and future consequences of incorporating AI in the framework of precision medicine through a complete narrative analysis.