Open research questions in Ferroptosis and cancer prognosis

What the literature leaves open

• However, the precise genetic switches that regulate ferroptosis sensitivity within specific immune cell lineages remain poorly characterized due to the resolution limits of bulk tissue analysis.

  Single-cell genetic architecture prioritizes GSTM1 as a candidate regulator of T-cell ferroptosis in NSCLC · 2026 · DOI

• Vitamin K was recently identified as a suppressor of ferroptosis and cardiovascular calcification, but whether ferroptosis links vitamin K status to disease progression in AS remains unknown.

  Vitamin K2 Limits Ferroptosis-Associated Lipid Peroxidation and Attenuates Aortic Valve Stenosis · 2026 · DOI

• 31 Although mTOR-mediated ferroptosis inhibition is known to promote tumor progression,32 the underlying mo- lecular mechanism remains to be fully elucidated.

  Targeting the 4EBP1/HSP90β/Nrf2 Axis Sensitizes β-catenin-mutant Hepatocellular Carcinoma to mTOR Inhibitors via Ferroptosis Induction · 2026 · DOI

• Intracellular iron homeostasis is increasingly recognized as a regulator of cancer cell behavior, but how iron distribution influences extracellular matrix (ECM) organization and invasion remains poorly understood.

  A DMT1-dependent iron-endoplasmic reticulum-extracellular matrix axis regulates cancer cell invasion · 2026 · DOI

• Furthermore, the function of MINK1, as a marker of oxidative stress-related gene signature, in the development of PCa has not been further verified in vivo, and its downstream regulatory pathways in PCa remain unexplored.

  Identification of the oxidation stress-related gene signatures and functional verification of MINK1 in prostate cancer cells · 2026 · DOI

• Abstract Ferritin, composed of heavy chain (FTH1) and light chain (FTL) subunits, is a key intracellular iron storage protein, but the origin and biological role of extracellular ferritin (ex-ferritin) remain poorly understood.

  Targeting macrophage ferritin heavy chain mitigates ferroptosis and lung injury in experimental acute respiratory distress syndrome · 2026 · DOI

• In this study, leveraging the synergy between lysosomal storage disorders and ferroptosis was not limited to AML treatment and may provide innovative solutions for a variety of treatment-refractory malignancies.

  Ferumoxytol enhances NF-κB-responsive GBA-targeted ferroptosis gene therapy in acute myeloid leukemia · 2026 · DOI

• emerging the the of investigations. Sesamin, a in pathways associated with Our network pharmacology analysis suggested that Yishen Huoxue Huatan formula and its active constituents are markedly enriched lipid metabolism, inflammation, and cell death, with potential associations with m6A regulatory factors. This provided a directional framework for subsequent mechanistic lignan compound derived from sesame oil, has been widely shown to exert multiple pharmacological effects, such as antioxidant, antiinflammatory, lipid-modulatory, and endothelial-protective properties, and has shown promising therapeutic potential in cardiovascular diseases (Dalibalta et al., 2020; Ghaderi et al., 2023; Majdalawieh et al., 2020). Prior investigations have directly demonstrated the ability of sesamin to mitigate atherosclerosis in animal models (Hadipour et al., 2023). For example, Wu et al. reported that sesamin reduced aortic atherosclerotic in ApoE-deficient mice by suppressing ICAM-1 expression (Wu et al., 2010). Nakamura et al. further showed that sesamin alleviated hepatic inflammation induced by a diet enriched in fat and cholesterol and decreased plasma platelet-activating factor acetylhydrolase (PAF-AH) activity, thereby decreasing LDL susceptibility to oxidation (Nakamura et al., 2020). lesion area that sesamin can These studies laid a solid foundation for the present work; however, sesamin, the precise molecular mechanisms of particularly those involving epigenetic regulation and novel forms of regulated cell death, remained largely unexplored. Although previous reports have suggested inhibit ferroptosis by downregulating HMOX1, FoxO1, or the Nrf2/ SLC7A11/GPX4 pathway (Ren et al., 2025; Ren et al., 2021; Yang et al., 2025; Zhu et al., 2025), whether sesamin exerts its antiatherosclerotic effects through modulation of ferroptosis and whether this process is linked to m6A RNA methylation had not been previously reported. Our subsequent in vivo and in vitro experiments demonstrated that sesamin significantly attenuates aortic lipid deposition and pathological injury in ApoE−/− mice while its potent antilipid profiles, confirming atherosclerotic efficacy. More importantly, this research provides, to our knowledge, the first mechanistic support linking sesaminmediated m6A dysregulation to ferroptosis-related endothelial injury during AS progression. In both animal and cellular models, sesamin reversed ox-LDL–induced increases in global m6A levels and ameliorated key features of ferroptosis, including iron accumulation, lipid peroxidation, and impairment of the antioxidant defense system (GPX4/xCT).

  Sesamin attenuates atherosclerosis by alleviating vascular endothelial ferroptosis-related injury via m6A-dependent regulation of SREBF1 expression · 2026 · DOI

• Future investigations incorporating these pharmacological inhibitors are warranted to further substantiate the ferroptotic dependency of the observed renal injury and fully elucidate the therapeutic spectrum of CHR.

  Chrysophanol ameliorates ferroptosis in acute kidney injury by promoting SIRT3-mediated NRF2 deacetylation · 2026 · DOI

• BackgroundWhile -synuclein (-syn) accumulation and iron dysregulation are hallmarks of Parkinsons Disease, the adaptations that enable neuronal survival under chronic protein stress remain unclear.

  Chronic alpha-Synuclein Over-Expression and Ceruloplasmin Challenge Promote Distinct Iron and Redox Responses in M17 Cells · 2026 · DOI

• BackgroundDespite epidemiological interest in aspirins chemopreventive potential against glioma, the underlying multi-layered molecular mechanisms -- spanning COX-2/PGE2 signaling, iron metabolism, ferroptosis, epigenetic regulation, and the NEO1/hepcidin regulatory axis -- have not been systematically characterized at the multi-omics level.

  Multi-Omics Integrative Analysis of the Aspirin-Gut-Brain-Glioma Axis: Transcriptomic, Proteomic, Epigenetic, Mendelian Randomization, and Single-Cell Transcriptomic Evidence Converges on NEO1/Hepcidin Iron Reprogramming and Ferroptosis Vulnerability · 2026 · DOI

• Mitotic catastrophe (MC) is a key biological axis, but externally validated MC-related gene (MCRG) signatures integrating immune and pharmacologic annotations remain lacking.

  Mitotic catastrophe–related six-gene signature predicts prognosis, tumor immune landscape, and therapeutic response in lung adenocarcinoma · 2026 · DOI

• ABSTRACT Aluminum oxide nanoparticles (Nano‐Al 2 O 3 ) are widely used engineered nanomaterials, but their neurotoxic effects and underlying mechanisms remain incompletely understood.

  Nicotinamide Mononucleotide Ameliorates Nano‐Aluminum Oxide‐Induced Cognitive Impairment and Ferroptosis via the GSH/GPX4 Axis · 2026 · DOI

• Abstract The prognostic values of cuproptosis-related genes (CRGs) in gastric cancer with lymph node metastasis (GCLM), especially in the tumor immune microenvironment (TIME), remain unclear.

  FDX1 as a predictive biomarker and therapeutic target for lymph node metastasis in gastric cancer · 2026 · DOI

• Several caveats constrain current interpretations. First, the majority of functional evidence derives from cell line overexpression or knockdown models, which fail to recapitulate clonal heteroge- neity and stromal complexity. Second, isogenic models systemati- cally comparing p53-wildtype versus p53-mutant backgrounds in the same cancer type are lacking, precluding definitive causal attribution of substrate switching. Third, the absence of single-cell resolution datasets mapping OTUD7B expression to specific tumor subpopulations obscures whether its functional duality reflects cell- intrinsic programs or microenvironmental adaptation. In summary, the context-dependent functional plasticity of OTUD7B arises from the integration of cell-type-specific substrate availability, post-translational enzymatic modulation, microenvironmental signal inputs, and genetic background-depen- dent network rewiring. Rather than representing an inherent molecular paradox, this plasticity reflects the sophisticated role of OTUD7B as a conditional signal integrator. Future research must move beyond binary oncogene or tumor-suppressor classifications and adopt multidimensional analytical frameworks to decode the precise contextual logic governing OTUD7B activity. These con- text-dependent outputs are schematically summarized in Figure 3.

  Research progress of OTUD7B: from structural function and disease mechanisms to clinical translation · 2026 · DOI

• Future studies should explore this potential non- canonical role of OVOL2 and investigate whether therapeutic agents like sulconazole might exert additional anti- tumor effects by influencing this lipid metabolic pathway. Although our current work establishes a central role for the glycolysis- lactate- lactylation axis in OVOL2- deficient CRC, it remains an open and intriguing question whether OVOL2's tumor- suppressive functions also extend to the modulation of lipid peroxidation.

  Sulconazole Suppresses Colorectal Cancer Immune Evasion by Inhibiting Glycolysis to Upregulate <scp>OVOL2 PARylation</scp> and Induce <scp>PANoptosis</scp> · 2026 · DOI

• (60, 63–65, 130, 132, 133) certain anesthetics provide the precipitating triggers. The protective effects of iron chelators, lipophilic antioxidants, and Nrf2-activating natural products in preclinical POCD models lend support to this concept. However, these observations remain largely correlative, and a critical unresolved question persists: does ferroptosis act as a proximal executor of synaptic damage and neuronal death, or is it merely a terminal removal mechanism for neurons already ren- dered non-functional by neuroinflammation and metabolic stress? Addressing this central question requires several lines of investiga- tion. First, temporally resolved studies are needed to determine whether lipid peroxidation and GPX4 inactivation precede or follow synaptic failure and microglial activation in the hours to days after surgery. Second, neuron-specific conditional knockout models (e.g., Gpx4 or Acsl4 deletion restricted to hippocampal neurons) should be employed to test whether blocking ferroptosis at the genetic level prevents POCD independently of anti-inflammatory effects. Third, the field must clarify which cell types—neurons, astrocytes, microglia, or oligodendrocytes— are the primary sites of ferroptotic damage, and whether intercellular propagation of lipid peroxides contributes to disease progression. Equally important are the translational challenges. Reliable biomarkers that can distinguish ferroptosis from other forms of oxidative injury in living patients are currently lacking. While QSM and T2 MRI can quantify regional brain iron content, and candidate lipid peroxidation products such as 15-HpETE-PE can be measured in cerebrospinal fluid, none has been prospectively validated for POCD risk stratification. Future clinical studies should integrate multimodal biomarkers—neuroimaging, CSF analysis, and blood- based assays—to construct predictive models and to monitor target engagement during therapeutic trials. Furthermore, key questions regarding therapeutic intervention remain unanswered: Is there a critical temporal window beyond which anti-ferroptotic therapy becomes futile? Would combining ferroptosis inhibitors with anti- inflammatory agents yield synergistic benefits, or merely add toxicity? Can BBB-penetrant iron chelators or GPX4 activators be safely administered to frail elderly surgical patients without com- promising systemic iron homeostasis or wound healing? Answers to these questions will determine whether ferroptosis-targeted thera- pies can progress from promising preclinical candidates to clinically meaningful interventions. Ultimately, the ferroptosis-centric model of POCD represents an exciting but still developing framework. The uncertainties outlined above should not be viewed as weaknesses of the hypoth- esis, but rather as guideposts for the next generation of mechanistic and translational research. It is only through carefully designed studies that directly test causality, establish temporal dynamics, and bridge the gap between animal models and human disease that the true role of ferroptosis in POCD will be elucidated—and its therapeutic potential realized.

  Ferroptosis: an emerging key mechanism linking aging, surgical and anesthetic exposure to postoperative cognitive dysfunction · 2026 · DOI

• The hypothesis that ferroptosis functions as a central pathogenic mechanism in POCD is compelling but requires more rigorous validation before it can be considered an established framework.

  Ferroptosis: an emerging key mechanism linking aging, surgical and anesthetic exposure to postoperative cognitive dysfunction · 2026 · DOI

• Based on the understanding of ferroptosis’s core role in POCD pathogenesis, intervention strategies targeting different nodes of the ferroptosis pathway hold considerable therapeutic promise. However, nearly all of these strategies are at the preclinical stage, and their translation to clinical practice faces significant hurdles. 5.1 Targeting iron metabolism: iron chelators Iron chelators, which bind and sequester excess intracellular free iron, thereby cutting off the substrate for the Fenton reaction at its source, represent a classic strategy for directly inhibiting ferroptosis. Deferoxamine (DFO), a first-generation iron chelator, has demonstrated neuroprotective effects in several POCD-related models. Li et al.

  Ferroptosis: an emerging key mechanism linking aging, surgical and anesthetic exposure to postoperative cognitive dysfunction · 2026 · DOI

• 30 A previous study demonstrated that kaempferol inhibits RA-FLS proliferation and reduces TNF-α secretion, but the exact mechanisms remain to be further investigated.

  Kaempferol suppresses fibroblast-like synoviocyte proliferation in rheumatoid arthritis by targeting glutamate-cysteine ligase modifier subunit to inhibit ferroptosis resistance · 2026 · DOI

• Our study is limited by reliance on publicly available datasets without experimental molecular validation of gene expression or bio- logical mechanisms. In the literature review of studies conducted on hub genes and shared genes, a study may have been conducted that was not mentioned in this study. Furthermore, further high-quality biological research with large sample sizes is required to validate our findings. Moreover, there is limitation on mechanistic insights in our study that could be acknowledge, further research should validate mechanistic importance of these biomarkers and correspondence pathways.

  Identification of STEAP4, EPC1, and CLEC1B as non-invasive candidate biomarkers for hepatocellular carcinoma using integrated bioinformatics analysis · 2026 · DOI

• Conflict of interest OxLDL-induced ferroptosis and pyroptosis represent intercon- nected cell death mechanisms driving inflammation and plaque insta- bility in atherosclerosis. The discovery of bidirectional crosstalk— GSDMD promoting LPO and ferroptotic DAMPs activating NLRP3 —reveals a previously unrecognized positive feedback loop that ampli- fies vascular inflammation. This integrated perspective provides a mechanistic framework for understanding the persistent inflammatory component of atherosclerosis and identifies multiple therapeutic targets. Several questions warrant future investigation. Single-cell tech- nologies should be applied to map the spatiotemporal dynamics of ferroptosis and pyroptosis at different disease stages and plaque regions. Development of reliable biomarkers reflecting ferroptosis- pyroptosis axis activation will facilitate patient stratification for targeted therapies. Clinical trials evaluating dual targeting strategies will help determine whether combined pathway inhibition offers The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

  OxLDL-induced ferroptosis and pyroptosis in atherosclerosis: a mini review · 2026 · DOI

• Jingjing Li, Xiaolan Xia, Kun Wang, Xia Xu and Chun Li* Department of Pharmacy, Wuhou District People’s Hospital, Chengdu, Sichuan Wuhou District Maternal and Child Health Hospital, Chengdu, Sichuan, China leads to Sepsis is a life-threatening disorder triggered by an unregulated host reaction to infection, and it represents a worldwide health dilemma given the scarcity of effective treatment strategies. Sepsis usually lethal multiorgan dysfunctions, including acute liver failure (ALF) and acute lung injury (ALI). Recent studies have found that altered programmed cell death (PCD) processes, including apoptosis, autophagy, ferroptosis, and pyroptosis, belong to key mechanisms that trigger sepsis-associated multiorgan disorders. Among them, ferroptosis is a unique mode of PCD characterized by the accumulation of iron-dependent reactive oxygen species (ROS) and lipid peroxidation. Mediating ferroptosis is a promising strategy against sepsis. Recently, studies have identified multiple natural products for treating sepsis-associated lung and liver injuries by targeting ferroptosis. Here, we provide an overview of the mechanisms and potential therapeutic targets underlying ferroptosis in sepsis. The natural products with ferroptosis targeting will be summarized. Notably, most current evidence supporting the therapeutic potential of natural products is derived from preclinical investigations, and high-quality clinical data remain scarce, requiring further validation for clinical translation. We hope this study provides new perspectives for the future treatment of sepsis-induced ALI and ALF.

  Natural products in treating sepsis-associated lung and liver injuries by mediating ferroptosis, current progress, and future perspective · 2026 · DOI

• DCM pathogenesis has evolved into a complex dynamic network. The emerging concepts of “metabolic–structural coupling” and “metabolic memory” reveal underlying reasons for the limitations of previous therapies. Targeting ferroptosis, cellular senescence, and metabolic regulators like FXR are promising new directions. However, these strategies face challenges: most targets lack human validation, clinical trial evidence is often from small samples, and the clinical heterogeneity of DCM demands better biomarkers for precise stratification. Within this framework, met- abolic-structural coupling explains how metabolic stress directly impairs contraction, while metabolic memory accounts for disease persistence despite glucose control—together bridging molecular pathways to clinical phenotypes. Future research must apply multi- omics technologies to human samples and develop more represen- tative disease models to accelerate preclinical validation. The ultimate goal is a paradigm shift from “one disease, one treatment” to “one disease, multiple subtypes, personalized therapy”.

  Pathogenesis of diabetic cardiomyopathy and emerging therapeutic strategies: a network-based perspective · 2026 · DOI

• The pharmacokinetic characteristics of BGBP remain unclear, and future research should focus on its bioavailability. Future studies should investigate the inflammation-related pathways and their therapeutic targets. Future research should explore the synergistic eects of BGBP and other neuroprotective agents, investigate the eÿcacy of BGBP in chronic spinal cord injury or aged animal models (12), and examine the specific target sites of BGBP within the iron metabolism regulatory network. 1850363 study; therefore, actual exposure levels at the target site remain unknown. The gastrointestinal stability and oral bioavailability of BGBP also remain to be characterized, which is a common limitation in peptide-based nutritional intervention studies (40). However, the role of inflammatory cascades in SCIRI remains unclear.

  Bitter gourd bioactive peptide alleviates neuronal ferroptosis after spinal cord ischemia-reperfusion injury, combined with emerging cell and animal models · 2026 · DOI

Most-cited papers in Ferroptosis and cancer prognosis

• The roles of ferroptosis in cancer: Tumor suppression, tumor microenvironment, and therapeutic interventions · Cancer Cell · 2024 · 504 citations
• GPX4, ferroptosis, and diseases · Biomedicine & Pharmacotherapy · 2024 · 351 citations
• 7-Dehydrocholesterol dictates ferroptosis sensitivity · Nature · 2024 · 331 citations
• Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis · Cell · 2024 · 327 citations
• Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma · Acta Pharmacologica Sinica · 2020 · 275 citations
• Ferroptosis inhibitor liproxstatin-1 alleviates metabolic dysfunction-associated fatty liver disease in mice: potential involvement of PANoptosis · Acta Pharmacologica Sinica · 2022 · 206 citations
• Gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition · Nature Cell Biology · 2024 · 190 citations
• The Metabolism of Neuronal Iron and Its Pathogenic Role in Neurological Disease: Review · Annals of the New York Academy of Sciences · 2004 · 184 citations
• Targeting carnitine palmitoyl transferase 1A (CPT1A) induces ferroptosis and synergizes with immunotherapy in lung cancer · Signal Transduction and Targeted Therapy · 2024 · 178 citations
• Mime: A flexible machine-learning framework to construct and visualize models for clinical characteristics prediction and feature selection · Computational and Structural Biotechnology Journal · 2024 · 151 citations

Most recent work

• Ferroptosis as a Nexus in Skeletal Muscle Pathophysiology: From Molecular Networks to Precision Medicine · The FASEB Journal · 2026
• ALDH1L2 induces resistance to chemotherapy in small cell lung cancer by inhibiting ferroptosis · Redox Biology · 2026
• Ferroptosis in compromised bone healing after trauma: from the iron/ROS microenvironment to non-union and bone defect reconstruction · Frontiers in Medicine · 2026
• Role of ferroptosis on immunotherapy in breast cancer · Molecular Biology Reports · 2026
• Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability · Nature Cell Biology · 2026
• OLFM4 mediating ischemia/reperfusion-induced kidney injury by regulating renal tubular epithelial cells ferroptosis via GPX4 · Molecular Biology Reports · 2026
• Implications of ferritinophagy in cardiovascular diseases and its pharmacological modulation: underlying mechanisms and clinical translation strategies · Cellular & Molecular Biology Letters · 2026
• Self-assembled nanoparticles overcoming hypoxic and acidic microenvironment to synergistically potentiate ferroptosis in triple-negative breast cancer · International Journal of Pharmaceutics · 2026
• Stress granules restrain ferroptosis by sequestering ferritin · Nature Cell Biology · 2026
• Identification of STEAP4, EPC1, and CLEC1B as non-invasive candidate biomarkers for hepatocellular carcinoma using integrated bioinformatics analysis · Biotechnology Reports · 2026

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