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Open research questions in Ubiquitin and proteasome pathways

127 unresolved questions extracted from the limitations and future-work sections of 273 Ubiquitin and proteasome pathways papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • The study identifies the challenge of understanding the molecular mechanisms that regulate intracellular signaling and antimicrobial pathways in Mtb-infected macrophages. The complexity of the GID/CTLH E3 ligase complex and its substrate repertoire is a challenge. The study highlights the need to develop novel strategies to treat or prevent TB.

    Ubiquitylation by the GID/CTLH complex regulates the metabolic and innate immune response of macrophages to infection by Mycobacterium tuberculosis · 2026 · DOI

  • The study faces the challenge of elucidating the role of Ubc9 during spermatogenesis in mammals. The research needs to overcome the difficulty of constructing a germ cell-specific conditional Ubc9 knockout mouse model. The study has to address the complexity of analyzing the effects of Ubc9 on male fertility and testicular development.

    Ubc9 Mediates SUMO2/3 Modification to Regulate Meiosis in Male Mice · 2026 · DOI

  • The role of Ubc9 has yet to be elucidated during spermatogenesis in mammals. The mechanisms of Ubc9-mediated SUMOylation in spermatogenesis are not well understood.

    Ubc9 Mediates SUMO2/3 Modification to Regulate Meiosis in Male Mice · 2026 · DOI

  • However, the non cell cycle vulnerabilities created by RB1 loss remain incompletely understood.

    Glutamine-regulated VCP acetylation creates a proteostasis vulnerability in RB1-deficient tumor · 2026 · DOI

  • However, the mechanism responsible for PD-1 deubiquitination and T cell dysfunction remains unclear.

    Deubiquitinase USP24 activated by IL-6/STAT3 enhances PD-1 protein stability and suppresses T cell antitumor response · 2025 · DOI

  • However, the role of UHRF1 in OSCC and its regulation by cigarette smoking remains unclear.

    Ubiquitin-like with phd and ring finger domains 1 as a potential therapeutic target in smoking-associated oral squamous cell carcinoma · 2025 · DOI

  • Hepatocellular carcinoma (HCC) frequently develops resistance to CD8+ T cell-based immunotherapy, yet the mechanisms driving this immune evasion remain poorly understood.

    USP14-mediated metabolic competition impairs CD8+ T cell immunosurveillance in hepatocellular carcinoma · 2025 · DOI

  • Further research into the pharmacological inhibition of UBR4 could open promising avenues for developing effective antitumor therapies targeting LUAD.

    Tumor-promoting UBR4 coordinates impaired mitophagy–associated senescence and lung adenocarcinoma pathogenesis · 2025 · DOI

  • However, the fundamental pathway coordinating senescence and neoplastic transformation remains unclear.

    Tumor-promoting UBR4 coordinates impaired mitophagy–associated senescence and lung adenocarcinoma pathogenesis · 2025 · DOI

  • PI-resistant MM cells are generally considered less immunogenic than sensitive cells, but their immunogenicity and associated anti-tumor immune responses are not fully understood.

    Altered Immunogenicity of Proteasome Inhibitor-Resistant Myeloma Cells in the 5T33MM Model 9271 · 2025 · DOI

  • Although deubiquitinating enzymes are implicated in tumorigenesis and progression, the specific role of ubiquitin specific peptidase 21 (USP21) in PCa remains unclear.

    USP21/YBX1/HIF1-α promotes the progression of prostate cancer · 2025 · DOI

  • BACKGROUND: Ubiquitination, small ubiquitin-related modifiers, and NEDDylation are now found to function in cancer biology; however, its role in the oral cancer patients remains unclear.

    Ubiquitination, SUMOylation , and NEDDylation related genes serve as prognostic and therapeutic biomarkers for oral squamous cell carcinoma · 2024 · DOI

  • The protein inhibitor of activated signal transducer and activator of transcription 2 (PIAS2) is known to undergo post-translational modifications, yet its impact on oral cancer remains unclear.

    Protein inhibitor of activated signal transducer and activator of transcription 2 is an oncoprotein in oral squamous cell carcinoma and related to cigarette smoking - An in vitro study · 2024 · DOI

  • The effects of global protein SUMOylation on chemoresistance in colorectal cancer (CRC) remains to be investigated.

    RREB1-mediated SUMOylation enhancement promotes chemoresistance partially by transcriptionally upregulating UBC9 in colorectal cancer · 2024 · DOI

  • Ubiquitin and polyubiquitin chains modulate UBQLN2's phase separation in a linkage-dependent manner, suggesting a possible link to substrate fate determination, but polyubiquitinated substrates have not been examined directly.

    Phase separation of polyubiquitinated proteins in UBQLN2 condensates controls substrate fate · 2024 · DOI

  • As an important active ingredient in traditional Chinese medicine, celastrol exhibits a wide range of biological activities, yet its mechanism remains unclear.

    Degradation‐Based Protein Profiling: A Case Study of Celastrol · 2024 · DOI

  • While the WW domain-containing coiled-coil adaptor (WAC) protein is primarily associated with transcriptional regulation and autophagy, its involvement in MSC osteogenesis remains unclear.

    WAC Facilitates Mitophagy‐mediated MSC Osteogenesis and New Bone Formation via Protecting PINK1 from Ubiquitination‐Dependent Degradation · 2024 · DOI

  • However, there are few studies on the functional characteristics of the UBP gene family in the important staple crop, maize (Zea mays L.

    Genome-wide identification and expression analysis of Ubiquitin-specific protease gene family in maize (Zea mays L.) · 2024 · DOI

  • However, the regulatory mechanism of STUB1 on ferroptosis and PTX resistance in OC remains unclear.

    STUB1 suppresses paclitaxel resistance in ovarian cancer through mediating HOXB3 ubiquitination to inhibit PARK7 expression · 2024 · DOI

  • Many aspects of deubiquitylation of polyubiquitylated substrates by Rpn11 remain unclear (Forster et al.

    Comparison of two UPS regulators: the 26S proteasome LID and the COP9 signalosome · 2024 · DOI

  • The reported literature underscores the therapeutic potential of MAO-B inhibitors as versatile anticancer agents, warranting further investigation to optimize their efficacy and specificity across various malignancies.

    Targeting MAO-B with Small-Molecule Inhibitors: A Decade of Advances in Anticancer Research (2012–2024) · 2024 · DOI

  • Despite the downregulation of CaMKKβ in DKD pathology, the underlying mechanism remains elusive.

    Aberrant expression of NEDD4L disrupts mitochondrial homeostasis by downregulating CaMKKβ in diabetic kidney disease · 2024 · DOI

  • Ubiquitin-specific protease 14 (USP14) is a key enzyme that regulates the deubiquitylation of DDR-related proteins, but whether USP14 participates in the pathogenesis of POI remains unclear.

    USP14 inhibition promotes DNA damage repair and represses ovarian granulosa cell senescence in premature ovarian insufficiency · 2024 · DOI

  • However, the pathogenesis of POI remains to be further elucidated, and specific targeted drugs which could delay or reverse ovarian reserve decline are urgently needed.

    USP14 inhibition promotes DNA damage repair and represses ovarian granulosa cell senescence in premature ovarian insufficiency · 2024 · DOI

  • UBXDF may affect tumour microenvironment (TME) and drugtherapy and should be investigated in the future.

    Exploring the role of ubiquitin regulatory X domain family proteins in cancers: bioinformatics insights, mechanisms, and implications for therapy · 2024 · DOI

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127 open questions have been extracted from the limitations and future-work passages of 273 Ubiquitin and proteasome pathways papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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