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Open research questions in Ubiquitin and proteasome pathways

565 gap statements mined from Ubiquitin and proteasome pathways papers in our 7.9M-paper local library, which holds 2,159 papers on the topic — drawn mostly from each paper's own stated research gap, future-work, challenge and limitation notes, and its abstract. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one.

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What the literature leaves open

  • The mechanisms by which HCC cells evade immune surveillance are not fully understood. The role of USP22 in HCC and its relationship to immune cell infiltration and phagocytosis is not well characterized.

    USP22-mediated phagocytic evasion promotes immune escape in TP53-inactivated hepatocellular carcinoma · 2026 · DOI

  • However, its precise function and molecular mechanisms involvement in CIRI remain unknown.

    USP11 Drives Cerebral Ischemia–Reperfusion Injury Via Promoting Ferroptosis by Deubiquitinating and Stabilizing ASK1 · 2026 · DOI

  • However, little is known about the role of the DTX E3 ligase DTX4 in substrate binding and ubiquitination.

    Structural and biophysical studies of human E3 ligase Deltex 4 · 2026 · DOI

  • The Catch domain of midnolin is essential for substrate recognition and binding, yet the underlying mechanism for its broad substrate specificity remains elusive.

    Biochemical and structural studies of the midnolin Catch domain bound with both wild-type and mutant IRF4 peptides reveal the molecular basis for its broad substrate specificity · 2026 · DOI

  • The importance of the deubiquitinase ubiquitin-specific peptidase 7 (USP7) in the etiology of various cancers is well recognized; however, its specific role and mechanisms of action in hepatocellular carcinoma (HCC) remain insufficiently elucidated.

    USP7 deubiquitinates Aurora B and promotes hepatocellular carcinoma progression · 2026 · DOI

  • Methyl-CpG binding domain protein 3 (MBD3) functions as a critical tumor suppressor in lung adenocarcinoma (LUAD), yet the ubiquitin-dependent mechanisms orchestrating its proteasomal turnover remain elusive.

    Ubiquitin-dependent degradation of MBD3 by TRIM59 promotes lung adenocarcinoma · 2026 · DOI

  • While the deubiquitinating enzyme USP46 is implicated in multiple tumor progression pathways, its specific role in oxaliplatin resistance remains undetermined.

    The USP46-MCM7-RAD51 axis confers oxaliplatin resistance in colon cancer by augmenting homologous recombination repair capacity · 2026 · DOI

  • However, little is known about the biological features and relevant molecular mechanism of Tripartite motif-containing 63 (TRIM 63) in melanoma.

    TRIM 63 Promotes the Malignant Behaviors of Melanoma Cells Through Ubiquitination of P 2 RY 1 · 2026 · DOI

  • However, the precise mechanisms by which NEDD4L functions in endothelial cells remain unclear.

    Therapeutic potential of targeting the NEDD4L-eEF1A1 axis in cancer therapy · 2025 · DOI

  • Although the preclinical and clinical efficacy of CFZ is obvious, the mechanism by which CFZ leads to cell death has not been fully elucidated.

    Using protein turnover assay to explore the drug mechanism of Carfilzomib · 2024 · DOI

  • However, the impact of the LTM motif on the interaction between the UBL domains of SHARPIN and HOIL-1L with HOIP remains unclear.

    AlphaFold2 assists in providing novel mechanistic insights into the interactions among the LUBAC subunits · 2024 · DOI

  • However, the function of PSMD14 in glioma and the underlying mechanism remain unclear.

    Deubiquitinase PSMD14 promotes tumorigenicity of glioblastoma by deubiquitinating and stabilizing β‐catenin · 2024 · DOI

  • The complex mechanisms of breast cancer immune evasion are not fully understood. There is a need for effective intervention measures targeting protein ubiquitination.

    Advances in protein ubiquitination modification and immune evasion of breast cancer · 2026 · DOI

  • Despite these considerable advances, our understanding of the full biological scope of arginylation remains limited.

    Expanding Biological Roles of Post-translational Arginylation · 2026 · DOI

  • The detailed molecular mechanisms underlying how RNF20 affects the mRNA or protein levels of components in the Ras-Raf-MEK-ERK cascade still need further investigations. How RNF20 is recruited to its target sites in different cells is not well understood.

    Decoding RNF20: an epigenetic modifier and beyond · 2026 · DOI

  • Side effects and off-target toxicities of drugs targeting RNF20 require more in-depth exploration and adequate validation. Systematic characterization of adverse effects in normal tissues and organ systems is needed to establish the clinical safety profile of RNF20-targeting therapeutics.

    Decoding RNF20: an epigenetic modifier and beyond · 2026 · DOI

  • To address these contradictory results, we employed an unbiased analysis of datasets deposited in GEO and TCGA and found that NUDT21 is overexpressed in most cancer cell types.

    Targeting NUDT21-mediated alternative polyadenylation of oncogenes ameliorates colorectal cancer malignancy and metastasis · 2026 · DOI

  • Despite significant progress in targeted therapy and immunotherapy for HCC, numerous challenges remain. For instance, although targeted drugs such as sorafenib and lenvatinib have extended patient survival, their objective response rate (ORR) as well as progression-free survival (PFS) still need improvement.

    The role of e3 ubiquitin ligases and deubiquitinating enzymes in hepatocellular carcinoma · 2026 · DOI

  • Together, these findings indicate that cells preserve proteasome-mediated proteostasis during acute glucose starvation, while NVJ membrane contact sites help sustain degradation capacity when metabolic resources are scarce.

    Proteasome-dependent degradation and nucleus-vacuole junctions sustain proteostasis during acute glucose starvation · 2026 · DOI

  • The need to understand the regulatory logic that governs the DDR.

    The phosphoproteomic landscape of the DNA damage response · 2026 · DOI

  • The paper had to overcome technical difficulties in detecting and quantifying USP38 expression in breast cancer tissues and cells. The study had to address the limited availability of research on USP38 in breast cancer.

    USP38 promotes breast cancer immune evasion and malignant progression by deubiquitinating and stabilizing PD-L1 · 2026 · DOI

  • Aurora kinase B (Aurora B) has been implicated in HCC progression, yet the regulation of its protein stability in this setting is poorly defined.

    USP7 deubiquitinates Aurora B and promotes hepatocellular carcinoma progression · 2026 · DOI

  • Investigate the underlying mechanisms of USP22 in stabilizing SPI1 protein, - Explore the therapeutic potential of USP22 in treating…

    USP22 alleviates oxidative stress-induced BMSCs senescence by stabilizing SPI1 protein · 2026 · DOI

  • Additional factors, such as SUMO’s “classical” SIM-dependent mode of interaction, its subcellular localisation, and the presence of other posttranslational modifications, including phosphorylation and acetylation, clearly contribute their own effects on phase separation and solubility.

    SUMO paralogues differentially affect phase separation and aggregation of intrinsically disordered proteins · 2026 · DOI

  • As a poorly characterized member of the plant-specific D-subgroup MAPKs, MAPK16 harbors a distinctive C-terminal domain that endows it with multiple critical functions, serving as a core positive regulator of maize resistance against F.

    A new plant SUMO ligase, MPEL1, synergizes with MAPK16 to regulate resistance against Fusarium pathogens · 2026 · DOI

Most-cited papers in Ubiquitin and proteasome pathways

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Open questions raised by papers listed on this page include: (1) The mechanisms by which HCC cells evade immune surveillance are not fully understood (“USP22-mediated phagocytic evasion promotes immune escape in TP53-inactivated…”, 2026); (2) Its precise function and molecular mechanisms involvement in CIRI remain unknown (“USP11 Drives Cerebral Ischemia–Reperfusion Injury Via Promoting Ferroptosis by…”, 2026); (3) Little is known about the role of the DTX E3 ligase DTX4 in substrate binding and ubiquitination (“Structural and biophysical studies of human E3 ligase Deltex 4”, 2026); (4) The Catch domain of midnolin is essential for substrate recognition and binding, yet the underlying mechanism for its broad substrate specificity remains elusive (“Biochemical and structural studies of the midnolin Catch domain bound with both…”, 2026); (5) Methyl-CpG binding domain protein 3 (MBD3) functions as a critical tumor suppressor in lung adenocarcinoma (LUAD), yet the ubiquitin-dependent mechanisms orchestrating its proteasomal turnover remain elusive (“Ubiquitin-dependent degradation of MBD3 by TRIM59 promotes lung adenocarcinoma”, 2026). 565 gap statements have been mined from Ubiquitin and proteasome pathways papers in our 7.9M-paper local library, which holds 2,159 papers on the topic; the gaps come from whichever of those papers state one. They are mostly the research gaps the authors state and the papers' abstracts, plus future-work, limitations and challenges passages. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one, so you can read the original claim in context.

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