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Open research questions in Cancer-related molecular mechanisms research

50 unresolved questions extracted from the limitations and future-work sections of 227 Cancer-related molecular mechanisms research papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Although traditionally considered non-coding, 21% of the ~190,000 annotated lncRNA transcripts contain poorly characterized open reading frames with unknown function.

    Signatures of micropeptides encoded by lncRNAs in cancer progression and metastasis · 2026 · DOI

  • Conclusion This study systematically profiles the molecular landscape of dysfunctional plasma cells within the HCC TME, confirms a correlation between FTH1 overexpression and plasma cell exhaustion, and provides correlative evidence to support further research on liver cancer immunotherapy targeting plasma cell immunity.

    Ferritin heavy chain 1 expression is correlated with plasma cell exhaustion and acts as a prognostic correlative marker in hepatocellular carcinoma · 2026 · DOI

  • Background Immunotherapy has emerged as a breakthrough in cancer treatment; however, the functional status of B lineage cells within the tumor microenvironment (TME) remains poorly characterized.

    Ferritin heavy chain 1 expression is correlated with plasma cell exhaustion and acts as a prognostic correlative marker in hepatocellular carcinoma · 2026 · DOI

  • Given the marked regulatory roles of lncRNAs in tumor cell senescence, the development of a SenRLs prognostic signature for STAD remains warranted.

    A prognostic senescence‑related long non‑coding RNA signature identifies cold and hot tumors of stomach adenocarcinoma · 2026 · DOI

  • Yiwei Xiaoyu granules (YWXY), a classical TCM formula, have demonstrated clinical benefit in chronic atrophic gastritis, yet their mechanistic actions in SPEM combined with SSDS remain unclear.

    Yiwei Xiaoyu granules mitigate spasmolytic polypeptide-expressing metaplasia-associated gastric mucosal damage by regulating WFDC2 and the miRNA-7/circRNA network · 2026 · DOI

  • While long noncoding RNAs (lncRNAs) play critical roles in hepatocellular carcinoma (HCC) pathogenesis, the regulatory mechanisms governing liver‐specific lncRNAs remain poorly defined.

    Epigenetic silencing of the liver‐specific <scp> lncRNA <i>LUNAR</i> </scp> promotes liver cancer progression via <scp>NOTCH</scp> activation · 2026 · DOI

  • ABSTRACT Tissue factor (TF; encoded by F3 ) is frequently overexpressed in ovarian clear cell carcinoma (OCCC), but the biological features of TF‐high tumors and their therapeutic implications remain poorly defined.

    Tissue Factor‐High Ovarian Clear Cell Carcinoma Shows Immune‐Cold Features and Preclinical Activity of Tisotumab Vedotin · 2026 · DOI

  • These data support further investigation of VEGF/VEGFR-directed therapy as a potential adjunctive strategy for patients with recurrent, unresectable, or surgically high-risk JNA.

    A Single-cell Atlas of Juvenile Nasopharyngeal Angiofibroma Reveals VEGF-Driven Angiogenic Remodeling as a Therapeutic Vulnerability · 2026 · DOI

  • LINC01133 has been implicated in regulation of multiple tumor-related mechanisms; however, its role in breast cancer, particularly in the triple-negative subtype, remains poorly characterized.

    LINC01133 knockout increases malignancy by migration mechanisms in Hs578T Triple-Negative Breast Cancer Cells · 2026 · DOI

  • Although long non-coding RNAs (lncRNAs) are increasingly recognized as regulators of immunity and viral pathogenesis, their roles in EBOV infection remain poorly understood.

    Ebola virus exploits host lncRNA LINC01740 to enhance ATF3 and suppress antiviral immune responses · 2026 · DOI

  • Malat1, a highly abundant and evolutionarily conserved lncRNA, is elevated in post-mortem brain tissue of human AUD subjects and rodents chronically exposed to ethanol; however, its causal contribution to AUD-relevant behaviors remains unknown.

    Global deletion of Malat1 alters alcohol consumption in a sex-specific manner · 2026 · DOI

  • Human papillomaviruses (HPV) rely on multiple host cell factors to replicate the viral genome, yet the contribution of host long noncoding RNAs (lncRNAs) to viral genome maintenance and amplification in the productive life cycle remains poorly understood.

    Differentiation-independent Activation of HPV Genome Replication by the lncRNA DINO · 2026 · DOI

  • Under stricter leave-one-gene-out and leave-one-small-RNA-out evaluation, the adapter exceeded the first-layer score baseline but only matched the majority-class baseline, underscoring that entity-level generalization is not yet established.

    A Two-Stage Interpretable Framework for Predicting Plant-Derived Small RNA Targets on Human 3'UTRs · 2026 · DOI

  • Mito-lncRNAs have emerged as key regulators of cardiac influencing bioenergetics, oxidative mitochondrial homeostasis, stress responses, calcium handling, and mitochondrial quality control. Dysregulation of molecules such as LIPCAR, MALAT1, RMRP, H19, and lncND5 has been linked to AMI, heart failure, Acta Pharmacologica Sinica (2026) 0:1 – 17 cardiomyopathy, and pulmonary hypertension [37, 41, 55, 88, 90]. Several of these transcripts demonstrate promising diagnostic and prognostic performance in early clinical studies. Preclinical models further suggest that correcting disease-associated mitochondrial lncRNA imbalances can partially restore mitochondrial function these findings and attenuate cardiac dysfunction. Together, position mito-lncRNAs as mechanistically informative candidates therapeutic for biomarker development modulation. and, potentially, compartment-specific mechanisms, However, the field remains in an early translational stage, and key challenges must be addressed systematically. Methodological limita- tions in defining true mitochondrial localization, an incomplete limited of understanding sequence conservation across species, and inefficient delivery to the heart and mitochondria remain major barriers. To address these challenges, future work should explicitly link each challenge to targeted experimental strategies. Detection and localization issues will require orthogonal validation, including rigorously controlled mito- chondrial fractionation, high-resolution RNA imaging, and emerging single-cell and spatial transcriptomic approaches. These methods help distinguish genuine mitochondrial signals from nuclear or cytoplasmic ones. Mechanistic ambiguity should be addressed with compartment- restricted gene-editing or silencing tools, RNA–protein interactome mapping, and structure–function analyses to identify the domains and interactions that drive mitochondrial phenotypes. To improve translational relevance, greater emphasis should be placed on human iPSC-derived cardiomyocytes, engineered cardiac tissues, organoids, and humanized or large-animal models that better capture human- specific lncRNA regulation. On the therapeutic front, progress will depend on developing cardiotropic and mitochondria-directed RNA delivery platforms—such as optimized viral vectors, lipid-based systems, or RNA constructs incorporating targeting motifs—alongside standardized frameworks for assessing biodistribution, immunogeni- city, and long-term safety. For biomarker translation, large, multi- center, and ethnically diverse prospective studies with harmonized assay protocols will be essential to determine whether mito-lncRNA signatures provide robust, incremental value over existing clinical these methodological and translational challenges are tools. addressed in a coordinated manner, mito-lncRNAs have the potential to contribute meaningfully to more precise risk stratification and to targeted modulation of mitochondrial dysfunction in cardiovascular disease.

    Echoes in the powerhouse: mito-lncRNAs contribution to cardiac function and disease · 2026 · DOI

  • Generali D, Berardi R, Caruso M, Cazzaniga M, Garrone O, Minchella I et al (2023) Aromatase inhibitors: the journey from the state of the art to clinical open questions.

    Long non-coding RNAs as modulators of endocrine therapy response in hormone receptor-positive breast cancer · 2026 · DOI

  • Long non-coding RNAs have emerged as critical regulators in cervical cancer pathogenesis, modulating therapeutic resistance through ceRNA networks, DNA damage repair, epithelial- mesenchymal transition, and key signaling pathways (e.g., PI3K/ AKT, Wnt/β-catenin). Their differential expression in patient specimens underscores significant potential as non-invasive biomarkers, while RNAi, ASOs, CRISPR/Cas9 systems, and exosome-mediated delivery offer promising therapeutic avenues. To accelerate clinical translation, four strategic priorities require focused investigation (Bray et al., 2024). Therapeutic targeting of the ceRNA axis: the predominant resistance mechanism, through ASOs or small molecule inhibitors to re-sensitize resistant tumors, ideally in combination with standard-of-care regimens (Duska et al., 2024). insights from other Mechanistic cross-fertilization leveraging Frontiers in Cell and Developmental Biology 16 frontiersin.org He et al. 10.3389/fcell.2026.1746979 gynecologic malignancies like ovarian and endometrial cancers to expedite understanding, while rigorously addressing cervical cancer- specific contexts including HPV integration dynamics and tumor immune evasion (Olusola et al., 2019). Rigorous clinical validation and current critical bottleneck: large-scale prospective trials are urgently warranted to standardize detection protocols, validate multi-marker liquid biopsy panels, establish safety and efficacy profiles of lncRNA-targeted interventions, and optimize tumor- specific delivery systems such as engineered exosomes and advanced nanoparticles to minimize off-target toxicity (Moody and Laimins, integration: capitalizing on lncRNAs as stable, specific biomarkers for early diagnosis and prognostic stratification via minimally invasive detection, deploying them as therapeutic targets to reverse radio- and chemoresistance, and utilizing lncRNA single nucleotide polymorphisms to identify genetically susceptible populations for risk-stratified prevention. Complementing these efforts, future research must prioritize large-scale, multi-center prospective studies with standardized protocols to reduce heterogeneity and enhance evidence reliability, alongside longitudinal monitoring of lncRNA expression dynamics throughout treatment to objectively assess therapeutic response and refine predictive accuracy. 2010). Personalized medicine Addressing these challenges through deeper elucidation of lncRNA biological networks will bridge the bench-to-bedside gap, unlocking their full potential as diagnostic biomarkers and therapeutic targets to improve outcomes for cervical cancer patients worldwide.

    The role of long non-coding RNAs in therapy resistance of cervical cancer and therapeutic potential · 2026 · DOI

  • While the study uses patient-derived organoid xenografts to model breast cancer progression, the intratumor heterogeneity and neoantigens in MALAT1-knockdown versus control PDO-X tumors have not been systematically characterized, limiting understanding of how MALAT1 loss affects MHC-I presentation and immune recognition in TNBC.

    Patient-derived organoid xenografts reveal the multifaceted role of the lncRNA MALAT1 in breast cancer progression · 2026 · DOI

  • Initial sequencing data was deposited at dbGaP (accession phs001486), but one critical accession number for the organoid RNA-seq dataset is incomplete (marked as blank), preventing full reproducibility of the alternative splicing analysis and differential gene expression results in the PDO-X models.

    Patient-derived organoid xenografts reveal the multifaceted role of the lncRNA MALAT1 in breast cancer progression · 2026 · DOI

  • The paper demonstrates antisense oligonucleotide (ASO) targeting of MALAT1 as a potential therapeutic approach for aggressive triple-negative breast cancer, but clinical efficacy and optimal ASO modifications (2'-constrained ethyl, phosphorothioate chemistry) for delivery and bioavailability in TNBC xenograft models have not been systematically evaluated.

    Patient-derived organoid xenografts reveal the multifaceted role of the lncRNA MALAT1 in breast cancer progression · 2026 · DOI

  • The study identifies MALAT1's multifaceted role in breast cancer progression using patient-derived organoid xenografts, but the mechanistic pathways by which MALAT1 regulates alternative splicing of specific oncogenic transcripts in triple-negative breast cancer remain incompletely characterized and require investigation of isoform-specific effects.

    Patient-derived organoid xenografts reveal the multifaceted role of the lncRNA MALAT1 in breast cancer progression · 2026 · DOI

  • Long non-coding RNAs (lncRNAs) are crucial in chronic liver diseases, but the specific molecular mechanism of lncRNAs in alcoholic fatty liver (AFL) remains unclear.

    Downregulation of long non-coding RNA AIRN promotes mitophagy in alcoholic fatty hepatocytes by promoting ubiquitination of mTOR · 2021 · DOI

  • Conclusions Tr-lncRNA–derived MPs represent a previously underexplored class of potentially functional molecules associated with cancer clinical annotation and may serve as biomarkers for disease progression.

    Signatures of micropeptides encoded by lncRNAs in cancer progression and metastasis · 2026 · DOI

  • Looking ahead, future research will focus on leveraging individual differences in non-coding RNAs to develop personalized COPD treatment strategies.

    Non-Coding RNA Regulates Pyroptosis in Chronic Obstructive Pulmonary Disease · 2026 · DOI

  • Although ferroptosis has been recognized as a critical pathological factor contributing to impaired diabetic wound healing, the therapeutic potential of resveratrol (Res), a natural polyphenol with well-documented antioxidant and anti-ferroptotic properties, remains underexplored in this context.

    Resveratrol Promotes Wound Healing by Enhancing Angiogenesis via Inhibition of Ferroptosis · 2025 · DOI

  • However, in most cases, the role of MIR31HG is documented only by one study and there is a lack of exact description of molecular pathways implicated in these processes, and for some of them, such as response to irradiation, no studies have been done.

    Host gene and its guest: short story about relation of long-noncoding MIR31HG transcript and microRNA miR-31 · 2023 · DOI

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50 open questions have been extracted from the limitations and future-work passages of 227 Cancer-related molecular mechanisms research 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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