Open research questions in Ferroptosis and cancer prognosis

What the literature leaves open

• Elucidating new molecular mechanisms driving ATC progression, - Developing novel therapeutic strategies for ATC

  Pin1 targets phosphorylated NCOA4 for K29/K48-linked ubiquitination to suppress ferritinophagy and ferroptosis in anaplastic thyroid cancer · 2026 · DOI

• The molecular mechanisms governing ferroptosis regulation in ATC remain poorly defined. The role of Pin1 in regulating ferritinophagy and ferroptosis is unknown.

  Pin1 targets phosphorylated NCOA4 for K29/K48-linked ubiquitination to suppress ferritinophagy and ferroptosis in anaplastic thyroid cancer · 2026 · DOI

• Investigating the role of ferroptosis suppressor protein 1 (FSP1) as a common target in inhibiting ferroptosis in hepatocellular carcinoma - Exploring strategies to enhance ferroptosis sensitivity

  Mechanistic insights into ferroptosis and its therapeutic potential in hepatocellular carcinoma · 2026 · DOI

• Limited understanding of the regulatory networks of ferroptosis in HCC. Lack of effective therapeutic strategies targeting ferroptosis. Need for a comprehensive roadmap for therapeutic translation.

  Mechanistic insights into ferroptosis and its therapeutic potential in hepatocellular carcinoma · 2026 · DOI

• The gap in current understanding of ferroptosis as a therapeutic target for gastrointestinal cancers. The need for effective therapeutic strategies to overcome drug resistance in gastrointestinal cancers. The limited understanding of the relationship between ferroptosis and tumor immunity.

  Targeting ferroptosis to overcome drug resistance in gastrointestinal cancers · 2026 · DOI

• Prioritizing intelligent nanoplatforms, - Gene-editing technologies, - The integration of single-cell sequencing with spatial transcriptomics to map organ-specific regulatory networks

  Breaking the cycle of fibrosis: Ferroptosis as a therapeutic target (Review) · 2026 · DOI

• Direct evidence in AU remains limited - Studies in retinal pigment epithelial cells, retinal vascular endothelial cells, and other retinal injury models should not be interpreted as direct proof in AU - The traditional M1/M2 dichotomy is increasingly considered insufficient to capture the mixed, intermediate, and context-dependent myeloid phenotypes

  Ferroptosis in autoimmune uveitis: potential links to blood–retinal barrier dysfunction and retinal inflammation · 2026 · DOI

• Priorities for preclinical validation - Investigation of ferroptotic-cell clearance and myeloid responses in AU - Elucidation of the role of ferroptosis in BRB dysfunction and retinal inflammation

  Ferroptosis in autoimmune uveitis: potential links to blood–retinal barrier dysfunction and retinal inflammation · 2026 · DOI

• Evaluating the translational potential of ferroptosis modulation - Discussing precision medicine approaches - Outlining key challenges for clinical application

  Ferroptosis-immune-metabolic axis in asthma: mechanistic crosstalk, endotype-specific regulation, and translational targeting · 2026 · DOI

• further investigation of the genetic factors associated with metabolism and their involvement in radiotherapy resistance, - exploration of the prognostic relevance of manganese metabolism in other types of cancer, - investigation of the role of TFs in regulating key genes

  Transcriptomics, identification, and testing of manganese metabolism-related genes in cervical squamous cell carcinoma · 2026 · DOI

• The lack of effective prognostic biomarkers for cervical squamous cell carcinoma. The limited understanding of the role of manganese metabolism in CSCC. The need for a systematic exploration of the prognostic relevance of manganese metabolism-related genes in CSCC.

  Transcriptomics, identification, and testing of manganese metabolism-related genes in cervical squamous cell carcinoma · 2026 · DOI

• The heterogeneous responses of patients to treatment. The incomplete understanding of the pathogenesis of severe MPP. The need for novel ferroptosis-related biomarkers and therapeutic targets.

  Integrative machine learning and transcriptomic analysis reveal a ferroptosis gene signature for pediatric Mycoplasma pneumoniae pneumonia · 2026 · DOI

• Protein-level, functional, in vivo, and clinical validation of the findings, - Development of ferroptosis-targeted interventions for personalized treatment strategies, - Investigation of the role of ferroptosis in other types of pneumonia

  Integrative machine learning and transcriptomic analysis reveal a ferroptosis gene signature for pediatric Mycoplasma pneumoniae pneumonia · 2026 · DOI

• Investigate direct ferroptotic death of susceptible epithelial cells in endometriotic precursor lesions, - examine the reproducible contribution of both iron and oxygen context to precursor-cell fitness, - study repeated exposure followed by clonal or cellular-population enrichment attributable to differential survival or expansion

  A coupled iron-hypoxia selection model for the evolution of endometriosis-associated ovarian clear cell carcinoma · 2026 · DOI

• Investigating the differences in TIME across distinct subtypes, - Developing a machine learning classifier to improve the clinical translational value of these molecular subtypes, - Validating the hypothesized benefits of combination drug in C1, C2, and C4 using cell lines, - Uncovering the differential drug response across different molecular cluster

  Delineation of molecular subtypes based on pathway activation signatures reveals intrinsic tumor heterogeneity and pan-cancer shared features · 2026 · DOI

• The candidate molecular targets and associations with the immune microenvironment in lung adenocarcinoma remain incompletely defined. The survival rates for patients with lung cancer remain suboptimal despite ongoing advancements in diagnostic and therapeutic strategies.

  Integrative multi-omics analysis prioritizes ALDH2 as a candidate Puerarin-associated target linked to macrophage infiltration in lung adenocarcinoma · 2026 · DOI

• Investigate the effects of different diets on ferroptotic signaling in DMD, - Examine the impact of GC treatment on ferroptosis in human DMD patients, - Study the role of GPX4 in maintaining redox balance in DMD

  Dystrophin Deficiency Creates a Pro-Ferroptotic Environment in Diaphragm of mdx Mice That Is Modified by Diet and Glucocorticoid Treatment · 2026 · DOI

• The lack of understanding of the role of ferroptosis in the progression of MASLD. The need for a conceptual framework for understanding hepatic ferroptosis. The absence of ferroptosis-targeted strategies in the treatment of MASLD.

  Ferroptosis in metabolic dysfunction-associated steatotic liver disease · 2026 · DOI

• Thus, ferroptosis represents a distinct, metabolically driven type of regulated cell death that integrates three central pathogenic mechanisms: iron dysmetabolism, accumulation of oxidizable PUFA phospholipids, and depletion of antioxidant defenses. The molecular architecture of ferroptosis in the liver in MASLD corre- sponds to four functional modules. The lipid module includes PUFA-mediated membrane remodeling (ACSL4, LPCAT3,

  Ferroptosis in metabolic dysfunction-associated steatotic liver disease · 2026 · DOI

• the study had a small sample size of 55 patients, - the study was limited to a specific cohort recruited during the December 2022-February 2023 Omicron epidemic peak in China, - the study did not account for other potential confounding factors

  Multi-omics reveals regulatory networks and critical early-warning factors for severe disease progression in diabetic patients infected with SARS-CoV-2 · 2026 · DOI

• further validation of the identified candidate biomarkers and pathway nodes is needed, - therapeutic strategies for diabetic patients with severe viral infections should be explored, - the bidirectional vicious cycle linking viral infection and metabolic disturbance should be further investigated

  Multi-omics reveals regulatory networks and critical early-warning factors for severe disease progression in diabetic patients infected with SARS-CoV-2 · 2026 · DOI

• The study did not analyze primary HHD tissue. The direction and consequences of ferroptosis-related pathways are strongly context-dependent. The study used a limited number of cells and samples.

  Exploratory ferroptosis-related transcriptomic patterns in dilated cardiomyopathy and pan-cancer datasets with H9c2 RT-qPCR assessment · 2026 · DOI

• the study does not provide a comprehensive understanding of the molecular mechanisms of LDS, - the sample size is limited to 146 participants, - the study only investigates breast cancer patients, - the study relies on peripheral blood samples, - the study does not provide a detailed analysis of the underlying biological processes

  Multi-omics graph attention network reveals neuro-immune-tumor pathways in breast cancer liver depression syndrome · 2026 · DOI

• further investigation of the molecular mechanisms of LDS, - expansion of the study to include larger and more diverse populations, - exploration of the underlying biological processes, - investigation of the potential applications of MOGAT in other diseases, - integration of MOGAT with other machine learning approaches

  Multi-omics graph attention network reveals neuro-immune-tumor pathways in breast cancer liver depression syndrome · 2026 · DOI

• The role of palmitoylation in DLBCL, particularly in relation to the immune microenvironment, is unclear. Current prognostic models do not fully account for molecular heterogeneity. There is a need for a deeper understanding of the molecular mechanisms underlying DLBCL tumorigenesis and progression.

  A palmitoylation-related signature predicts prognosis and immune microenvironment features in diffuse large B-cell lymphoma · 2026 · DOI

Most-cited papers in Ferroptosis and cancer prognosis

• Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization · Science · 2004 · 4,019 citations
• The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis · Nature · 2019 · 3,395 citations
• Ferroptosis as a p53-mediated activity during tumour suppression · Nature · 2015 · 3,123 citations
• FSP1 is a glutathione-independent ferroptosis suppressor · Nature · 2019 · 3,077 citations
• CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy · Nature · 2019 · 2,562 citations
• Targeting ferroptosis as a vulnerability in cancer · Nature reviews. Cancer · 2022 · 2,102 citations
• Ferroptosis in cancer therapy: a novel approach to reversing drug resistance · Molecular Cancer · 2022 · 1,264 citations
• Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies · Signal Transduction and Targeted Therapy · 2024 · 899 citations
• CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4 · Cancer Cell · 2022 · 863 citations
• Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects · Signal Transduction and Targeted Therapy · 2024 · 696 citations

Most recent work

• Reactive oxygen species (ROS) in cancer: from mechanism to therapeutic implications · Signal Transduction and Targeted Therapy · 2026
• Extracellular GPX4 impairs antitumor immunity via dendritic ZP3 receptors · Cell · 2026
• Ulcerative colitis: signaling pathways, therapeutic targets and interventional strategies · Signal Transduction and Targeted Therapy · 2026
• Ferroptosis-immune-metabolic axis in asthma: mechanistic crosstalk, endotype-specific regulation, and translational targeting · Frontiers in Immunology · 2026
• A GPX1-OSBPL8 axis mediates noncanonical in vivo ferroptosis and cancer growth suppression · Cell · 2026
• Ferroptosis inhibition enhances liver and lung graft function · Cell · 2026
• Cuproptosis-immunity crosstalk informs strategy to overcome immunotherapy resistance · Cell · 2026
• Iron-fueled ferroptosis: a new axis for immunomodulation to overcome cancer drug resistance—from immune microenvironment crosstalk to therapeutic translation · Frontiers in Immunology · 2026
• Stabilizing MARCH7 as a ferro-guardian against ferroptosis · Cell · 2026
• TRIM28 Is an E3 Ligase of IRP2 Suppressing Ischemia/Reperfusion–Induced Myocardial Ferroptosis · Circulation · 2026

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