Ferroptosis, characterized by iron-dependent lipid peroxidation, represents a promising therapeutic target for cancer treatment. Strategies that disrupt intracellular antioxidant systems to induce ferroptosis in cancer cells have been extensively explored. Herein, we developed a pH-responsive phototheranostic agent (designated as FSB4Ca NPs) by encapsulating conjugated boron dipyrromethene tetramers (B4) within ferric ion-sulfasalazine metallo-network polymer-coated calcium carbonate hollow nanoparticles. Sulfasalazine, a known ferroptosis inducer that inhibits System Xc--mediated cysteine influx, synergizes with ferric ion-driven glutathione (GSH) depletion to collectively amplify intracellular lipid peroxidation. In addition to serving as a second near-infrared (NIR-II) fluorophore for tracking the in vivo distribution of FSB4Ca NPs, B4 mediates a photothermal effect that significantly enhances lipid peroxidation induction by boosting the Fenton catalytic activity of ferrous ions. Combined with localized 915-nm laser irradiation, intravenously administered FSB4Ca NPs achieved substantial tumor suppression in mouse models, with a complete remission rate of 80%. This study establishes a facile strategy for developing long-circulating NIR-II phototheranostic agents with self-amplified lipid peroxidation induction capacity, enabling photothermally augmented ferroptosis for cancer therapy.

Abstract Ferroptosis, a form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides, is increasingly recognized as a critical pathogenic mechanism in various human diseases. Given the significant implication of ferroptosis in pathology, there is an urgent need to identify novel chemotypes with anti-ferroptotic activity. Recently, natural products have garnered attention as safe and effective sources for ferroptosis regulators. In this study, we identified Neohesperidin dihydrochalcone (NHDC), a flavonoid sweetener derived from citrus fruits, as a potent inhibitor of ferroptosis. We demonstrated that NHDC significantly restored cell viability in HT-1080 cells treated with Erastin, a System Xc− inhibitor. Mechanistically, NHDC treatment effectively mitigated the accumulation of lipid reactive oxygen species (ROS) and modulated the expression of ferroptosis-related proteins, including SLC3A2, SLC7A11, and PTGS2. Furthermore, NHDC exhibited a protective effect against ferroptosis induced by Sulfasalazine (SAS), another System Xc− inhibitor, by reverting SAS-induced lipid ROS levels. Interestingly, NHDC showed selectivity in its protective mechanism, distinguishing its activity from RSL3-induced ferroptosis pathways. Collectively, our findings demonstrate that NHDC acts as an effective anti-ferroptotic agent by targeting System Xc− inhibition. This study provides valuable insights into the therapeutic potential of NHDC as a natural candidate for the treatment of ferroptosis-related diseases. Citation Format: Bomi Han, Yi-Xi Gong, Seonghye Son, Eui Man Jeong, . Neohesperidin dihydrochalcone: A novel natural inhibitor of ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3667.

Ferroptosis is a regulated form of cell death that serves a pivotal role in tumor suppression. Whilst the ribonuclease activity of inositol-requiring enzyme 1α (IRE1α) is associated with the regulation of ferroptosis, the potential involvement of its kinase domain in this process remains elusive. Thus, the present study aimed to investigate the specific role of the IRE1α kinase domain in regulating ferroptosis in breast cancer, particularly in the triple-negative breast cancer (TNBC) subtype. To this end, it employed a combination of bioinformatic analysis of clinical datasets, pharmacological inhibition of IRE1α kinase and genetic overexpression models in TNBC cell lines. The present study demonstrated that endoplasmic reticulum to nucleus signaling 1 (ERN1; the gene encoding IRE1α) was significantly downregulated in breast cancer compared with that in normal tissues, and that lower ERN1 levels were associated with a worse prognosis of patients with breast cancer. This association persisted in human epidermal growth factor receptor 2-positive and TNBC subtypes. In TNBC, IRE1α kinase inhibitors (APY29 and sunitinib) markedly inhibited ferroptosis induced by system Xc- inhibition. Moreover, by constructing overexpression models of wild-type IRE1α (IRE1α-WT) and a kinase-dead mutant (IRE1α-K599A), it was demonstrated that IRE1α-WT overexpression significantly enhanced sensitivity to ferroptosis, whereas the kinase-dead mutant had no significant effect. Mechanistically, IRE1α kinase inhibition upregulated solute carrier family 7 member 11 (also known as xCT) expression and promoted glutathione (GSH) synthesis, thereby suppressing ferroptosis. Collectively, the present study reveals a new function of IRE1α kinase in the regulation of ferroptosis, highlighting the critical regulatory role of the IRE1α kinase-xCT-GSH axis in ferroptosis in TNBC. Thus, IRE1α kinase may have potential as a therapeutic target.

Flavonoid-mediated modulation of ferroptosis: therapeutic potential in gastrointestinal cancers.

Tme-responsive porphyrin-based Mn-MOF/Erastin nanotherapeutic synergistically triggers cascading ferroptosis for hepatocellular carcinoma therapy

Ferroptosis plays a critical role in postmenopausal osteoporosis (PMOP) pathogenesis, but targeted therapies remain limited. In this study, we have developed bone-targeting selenium-doped carbon dots conjugated with alendronate (ASCDs) with the dual functionality of suppressing ferroptosis and promoting osteogenesis. In vitro, ASCDs mitigated erastin-induced ferroptosis in osteoblasts and bone-marrow mesenchymal stem cells by activating the system Xc--GSH-GPX4 antioxidant pathway, which reduced lipid peroxidation and restored mitochondrial function. Furthermore, ASCDs induced ALP activation and mineralized nodule formation under ferroptosis conditions, and enhanced expression of osteogenic markers, including RUNX2, OPN, and OSX. In vivo, ASCDs demonstrated superior efficacy compared to non-targeted selenium-doped carbon dots (SCDs), significantly reversing trabecular bone loss in ovariectomized mice, reducing osteoclast activity, and suppressing ferroptosis in bone tissue. Proteomics and biochemical analyses further validated that ASCDs exert therapeutic effects by rescuing GPX4 expression and redox homeostasis. Such dual-functional carbon dots present a targeted strategy to treat PMOP by concurrently inhibiting ferroptosis and restoring bone formation.

The HIF-2 transcription factor mediates resistance to ferroptosis in pancreatic cancer.

The severe chemoresistance-caused high recurrence has made ovarian cancer (OVCA) the most lethal gynecological malignancy in clinical practice. Ferroptosis represents a promising therapeutic approach for OVCA, which could effectively overcome tumor resistance. Nevertheless, the traditional ferroptosis inducers lack specificity and selectivity, resulting in poor therapeutic effects. Here, we identified a novel tRNA-derived fragment, tRF-21-XSXMSL73E (tRF-21), which could serve as a ferroptosis inducer to efficiently suppress OVCA growth through dual inhibition of the system Xc-/glutathione (GSH)/peroxidase 4 (GPX4) axis without causing obvious side effects. Mechanistically, tRF-21 promotes SLC3A2 ubiquitination via SPOP E3 ligase and destabilizes SLC7A11 mRNA by disrupting NSUN2-mediated m5C methylation. This dual-inhibition effect on the system Xc-/GSH/GPX4 axis leads to GSH depletion, reactive oxygen species (ROS) accumulation, and ferroptotic cell death. To enhance therapeutic delivery, we engineered a pH-responsive nanoplatform (tRF-21@EPH) with an ellagic acid core, polyetherimide (PEI) intermediate layer, and hyaluronic acid shell, enabling nuclease protection and tumor-specific uptake. This system markedly improved tRF-21 efficacy with minimal toxicity, providing a novel RNA-based strategy for OVCA treatment.

Abstract Brain metastasis in breast cancer represents a devastating, end-stage event, with median survival measured in months. This underscores the urgent need for novel therapeutic strategies. Breast cancers that metastasize to the brain face a nutrient-poor and immune suppressive environment and considered an immue excluded or ‘cold’ tumor. These tumors exhibit metabolic reprogramming, relying heavily on acetate as a carbon source. The enzyme acetyl-CoA synthetase 2 (ACSS2) converts acetate into acetyl-CoA and has emerged as a critical regulator of this adaptation. Here, we show that breast cancer brain metastatic (BCBM) cells express significantly higher ACSS2 levels compared to their parental counterparts and that ACSS2 is required for BCBM growth in vivo. Mechanistically, ACSS2 promotes BCBM survival by suppressing ferroptosis, a form of immunogenic cell death (ICD), through E2F1-mediated regulation of the cystine-glutamate transporter SLC7A11. Treatment with our newly developed brain-penetrant ACSS2 inhibitor (ACSS2i) in a syngeneic BCBM model significantly reduced tumor growth in vivo. Consistent with inducing ICD, single-cell RNA sequencing analysis revealed increased infiltration of NK and T cells in ACSS2i–treated tumors, with elevated expression of CD8, CD4, and CD28. Furthermore, conditioned media from ACSS2 inhibitor-treated BCBM cells enhanced dendritic cell (DC) maturation in vitro, as indicated by upregulation of costimulatory molecules CD86 and CD40. Lastly, flow cytometry data shows that BCBM tumors treated with ACSS2 inhibitors increased immune infiltration of adaptive T and B cells, number of monocytes and DCs. Thus, targeting ACSS2 triggers ferroptotsis, reduced BCBM growth and reshapes the brain tumor microenvironment to enhance immune cell infiltration and potentially convert a ‘cold’ tumor into an immune-inflamed ‘hot’ tumor. Citation Format: Riley G. Young. Targeting ACSS2 promotes ferroptosis and immune cell infiltration in breast cancer brain metastases [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B066.

The absence of JK antigens carried by the erythroid urea transporter due to null alleles is well documented. To date, over 50 alleles have been identified and registered by the International Society of Blood transfusion (ISBT Blood Group Database). An elderly woman of European ancestry developed anti-JK1 (Jka) 3 days after the transfusion of two units of packed red blood cells (RBCs), one of which was from a JK:1 (or Jk(a+)) donor. The JK phenotype of the other unit was unknown. We report the identification of a novel JK*01 allele carrying the c.151+1G>C variant in the SLC14A1 gene that was shown to be responsible for the lack of JK1 (Jka) expression by functional analysis. Antibody identification was done using standard methods. The patient's plasma was tested with native or papain or trypsin-treated RBC. A direct antiglobulin test (DAT) was performed on the patient's RBC. Subsequently, the eluate using Gamma ELU-KIT II (Werfen, Norcross, USA) was tested in an indirect agglutination test (IAT) to identify a potential alloantibody. Genomic DNA was isolated from whole blood with NucleoMag (Macherey-Nagel, Hoerdt, France) according to the manufacturer's instructions. Genotyping was performed using the HEA BeadChip array (BioArray Solutions/Immucor-Werfen, Warren, New Jersey, USA) and Sanger sequencing (SLC14A1 coding exons 3 to 10 and flanking regions; 3500 Dx genetic analyzer, Thermo Fisher), as previously described.1 The effect of the variant was predicted in silico using SpliceAI2 and SPIP3 and reporter minigene splicing assay was performed to further investigate the effect of the variant in an in vitro model.4, 5 Anti-JK1 was identified in the patient's plasma by IAT. The DAT was 2+ with anti-C3d, and the eluate also contained anti-JK1, consistent with an allo-antibody due to a recent RBC transfusion. By the HEA Beadchip, the sample was found to be heterozygous (G/A) at position c.838 defining the JK1/JK2 antigen specificity, which is consistent with a JK*01/JK*02 genotype. According to the reference sequence NM_015865, Sanger sequencing of SLC14A1 confirmed c.838G/A in exon 8, and additionally detected the c.151+1G>C single nucleotide variant, which is located within the consensus donor splice site of intron 3, at the heterozygous state. This variant was predicted to disrupt splicing by in silico investigation (SpliceAI score: 0.71 [donor loss]; SPiP v2.1 score: 0.986 [Alter by SPiCE]). The deleterious effect was confirmed in vitro by the minigene splicing assay demonstrating the complete disruption of the constitutive donor splice site and the full skipping of SLC14A1 exon 3 (Figure 1, black arrowhead). Very importantly, this exon carries the methionine initiation codon. Therefore, it is thought that translation initiation cannot occur and no normal protein can be expressed from the novel allele carrying the c.151+1G>C variant. In this work, we describe the novel JK*01 N c.151 + 1 G>C null allele (Genbank accession number: PX849538) that disrupts the expression of the JK1 antigen in a patient of European descent who made anti-JK1 after being transfused with JK:1 RBC. This demonstrates, once again, that caution must be exercised when interpreting targeted genotyping results when antibodies are present. ISBT Blood Group Database (JK blood group system): blooddatabase.isbtweb.org/system/JK (accessed on January 12, 2026). Open access publication funding provided by COUPERIN CY26. The authors have nothing to report. The authors have disclosed no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ephx2 Deficiency Suppresses Chronic Obstructive Pulmonary Disease by Inhibiting Ferroptosis Caused by Cigarette Smoke via Regulation of the System Xc -/GSH/GPX4 Axis In Vivo.

The patient presented various neurological symptoms in her 50s, such as memory issues, insomnia, depression, and motor impairment. Diverse investigations were performed to identify the underlying causes on her neurological symptoms and understand her neuro- deteriorations. Clinical neurological and brain imaging analyses: CT, MRI and PET were performed on the patient. Blood was drawn for the whole-exome sequencing and functional studies with biomarker for amyloid-beta oligomers and SLC20A2 protein in plasma. Brain imaging revealed calcifications in multiple regions, including the subcortical white matter, basal ganglia, thalami, and dentate nuclei. Genetic analysis revealed a c.1152_1153delCA, p.Asn384Lysfs*30 variant in SLC20A2 gene. The decreased SLC20A2 protein levels in plasma in comparison to healthy controls suggested a loss-of-function mechanism from the mutation. The patient had a positive AlzOn result, indicating an increased tendency for amyloid oligomerization and suggesting a potential indirect link between SLC20A2 and amyloid-beta pathways. A novel frameshift mutation, Asn384Lysfs*30, in the SLC20A2 gene was identified in a patient with Primary Brain Calcification (PBC). This mutation was located in a critical large loop region of the protein, where other similar mutations (e.g., Gly366fs89, Ser385Ilefs*70) were previously reported. These findings indicated that mutations in SLC20A2 caused the reduced protein expressions, potentially resulting PBC through haploinsufficiency.

Castration-resistant prostate cancer (CRPC) is frequently resistant to conventional therapies and lacks effective treatment options. Although CRPC cells exhibit sensitivity to ferroptosis inducers, the mechanisms regulating ferroptosis remain unclear. Here, we identify nuclear factor I/B (NFIB) as a critical suppressor of ferroptosis in CRPC. NFIB is upregulated in CRPC tissues and cell lines, positively correlating with SLC3A2, a critical subunit of System Xc-. NFIB knockout enhances erastin-induced ferroptosis, marked by elevated Fe2 +, MDA, and ROS levels. Mechanistically, NFIB directly activates SLC3A2 transcription and forms nuclear condensates through intrinsically disordered regions at both the N-terminus (1-69) and C-terminus (173-495), with the C-terminal IDR additionally supporting nuclear localization. Moreover, SIRT7-dependent deacetylation of NFIB regulates acetylation at K65 within the N-terminal IDR, thereby tuning condensate dynamics. K65 mutation reduces condensate liquidity and weakens NFIB-driven SLC3A2 transcriptional activation, resulting in enhanced ferroptosis. In vivo, combined NFIB suppression and ferroptosis induction significantly inhibit tumor growth and increase lipid peroxidation in CRPC xenografts. These findings uncover a critical role of NFIB phase separation and acetylation in ferroptosis regulation and suggest NFIB as a promising therapeutic target in CRPC.

Short QT syndrome (SQTS) is an inherited channelopathy that can cause sudden cardiac death. Recent research has implicated mutations in the SLC4A3 gene as a cause of SQTS, but the mechanisms of shortened action potential duration (APD) and arrhythmia vulnerability have not been described. This study aims to evaluate the underlying pathophysiology causing a shortened APD and ventricular arrhythmia vulnerability in SLC4A3-associated SQTS through mechanistic studies of novel SLC4A3 mutations responsible for familial SQTS. This study evaluated the function and pathophysiology of two novel SLC4A3 variants (p.Arg370Cys and p.Lys531Thr) responsible for SQTS in their respective families. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from each index SQTS patient were developed, as well as an isogenic cell line with variant correction (using CRISPR/Cas9) and HEK 293T cells transfected with SLC4A3 expression constructs expressing either wild type (WT) SLC4A3 or the variants. SLC4A3-SQTS variants were physiologically characterized by patch-clamp analysis, Ca2+ imaging, single cell contraction, intracellular pH measurement, protein structure analyses, immunostaining, and optical mapping studies in a human organoid model. SQTS-hiPSC-CMs showed significantly shorter APD and a higher rate of arrhythmia-like events, as recorded by spontaneous action potentials, calcium transient imaging, and rhythmicity of visualized single cell contractions. SQTS-hiPSC-CMs exhibited decreased L-type calcium channel current (ICa-L), and significantly increased Na/Ca exchange current (INCX). Frequent delayed afterdepolarization (DAD) events were recorded from mutant cells but not WT or isogenic cell lines. The intracellular pH value was significantly higher (alkaline) in SQTS-hiPSC-CMs and in transfected heterologous cells expressing mutant SLC4A3, as compared to WT-SLC4A3. Experimental-induced alkalinization of WT-hiPSC-CMs by NH4Cl resulted in shortened APD, enhanced INCX, and reduced ICa-L, similar to observations in cells expressing mutant SLC4A3 proteins. Quinidine and sotalol were found to prolong APD and decrease the occurrence of arrhythmia-like events (DADs) in SQTS-hiPSC-CMs. In human cell models, SLC4A3 mutations responsible for SQTS result in loss-of-function leading to intracellular alkalinization, decreased ICa-L, and shortened APD, accounting for the clinical phenotype of short QT. Arrhythmic events in SLC4A3-associated SQTS are provoked by enhanced INCX evoking DADs.

Ferroptosis is a promising programmed cell death modality for cancer therapy, driven by iron overload and the accumulation of phospholipid peroxides that culminate in lethal membrane damage. Over the past decade, emerging evidence supports the concept that ferroptosis can be harnessed as an effective strategy to suppress tumor growth, particularly in therapy-resistant cancer cells undergoing epithelial-mesenchymal transition and in cancer stem cells. Given that ferroptosis is mechanistically and morphologically different from other known programmed cell death forms, increasing critical findings have shed light on mechanisms by which ferroptosis is regulated, and context-dependent cancer phenotype which is clinical relevant to ferroptosis. In this review, we summarize the basic biology of ferroptosis, including iron regulation and lipid metabolism, as well as key molecular mechanisms such as the system Xc⁻-GSH-GPX4, NADPH-FSP1-CoQ10 and GCH1-BH4 axis in fighting cancer. We also discuss crosstalk between ferroptosis and cuproptosis, disulfidptosis and autophagy, and outline how ferroptosis shapes the tumor immune microenvironment and responses to immunotherapy. More importantly, we highlight the clinical potential of ferroptosis induction via chemotherapy, radiotherapy, immunotherapy and nanomedicine-based delivery strategies, while summarizing common resistance mechanisms and safety considerations. Finally, we outline major challenges and pressing questions for clinical translation, including what are the molecular bases of ferroptosis, how can ferroptosis be leveraged for cancer therapy, how can ferroptosis be integrated with conventional therapies, and how to balance benefits and risks of ferroptosis-based therapy. Collectively, this review connects mechanistic insights with actionable intervention points for developing ferroptosis-based cancer therapies.

Ferroptosis is a regulated cell death pathway driven by the iron-dependent accumulation of reactive oxygen species (ROS) and lipid hydroperoxides. A major factor limiting the effectiveness of ferroptosis induction is the antioxidant activity of glutathione peroxidase 4 (GPX4). Herein, we reported SLC7A11-targeting proteolysis targeting chimeras (PROTACs) to deplete GPX4 and to augment oxidative stress within cancer cells. A bifunctional PROTAC, namely dSLC7A11, ws designed by conjugating the SLC7A11 inhibitor sulfasalazine to the CRBN ligand pomalidomide via an alkyl linker. The rational designed chimera effectively induced ubiquitin-mediated degradation of SLC7A11. Consequently, this inactivated cystine/glutamate antiporter (System Xc-), depleted GPX4, and amplified oxidative stress in cancer cells. Notably, dSLC7A11 exhibited superior antitumor efficacy over sulfasalazine alone, and achieved an effect of suppressing tumor growth by >65% in vivo. This study presented a SLC7A11-targeting PROTAC that disrupts the cellular antioxidant defense system, thus establishing a novel PROTAC-based approach for potent ferroptosis induction in cancer therapy.

Tripterygium glycosides reverse cisplatin resistance in epithelial ovarian cancer by activating ferroptosis via two different pathways.

The role of selenium in modulating sperm count and ferroptosis pathways in male reproductive health.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is increasingly recognized as a pivotal mechanism in the pathogenesis of acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS). Its core molecular machinery, including glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4), and the cystine/glutamate antiporter system Xc-, becomes dysregulated across various ALI subtypes, such as sepsis, ischemia-reperfusion, and COVID-19.This review delineates how ferroptosis contributes to ALI through iron overload, uncontrolled lipid peroxidation, and failure of antioxidant defenses, ultimately leading to pulmonary endothelial and epithelial cell death. We further summarize subtype-specific mechanisms and evaluate emerging therapeutic strategies, including ferroptosis inhibitors (e.g., liproxstatin-1), Nrf2 activators, and iron chelators, highlighting their potential for targeted intervention in ALI/ARDS.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited therapeutic options and a profoundly immunosuppressive tumor microenvironment (TME). Ferroptosis, a novel form of regulated cell death driven by iron-dependent lipid peroxidation, has emerged as a promising therapeutic avenue by targeting metabolic vulnerabilities in cancer cells. Notably, key ferroptotic pathways in PDAC involve iron accumulation, lipid peroxidation, and oxidative stress. Major defense systems include the System Xc⁻/GSH/GPX4, NAD (P)H-FSP1-CoQH2/VKH2, DHODH-CoQH2, and GCH1-BH4 pathways. Ferroptosis exhibits dual roles in PDAC, demonstrating both tumor-suppressive and oncogenic effects within TME. Ferroptosis-related biomarkers show promise for PDAC diagnosis and prognosis. Novel therapeutic strategies combining ferroptosis inducers with conventional treatments and nanoparticle-based delivery systems have shown encouraging results in preclinical studies. While ferroptosis-based therapies offer potential for PDAC treatment, challenges remain in translating these approaches to clinical practice. Therefore, this review provides a comprehensive synthesis of the mechanistic insights, therapeutic potential, and associated challenges of targeting ferroptosis in PDAC. It is necessary to identify specific biomarkers, mitigate side effects, and elucidate the complex interactions between ferroptosis and TME. Integrating ferroptosis modulation with existing therapies may lead to more effective, personalized treatment strategies for PDAC.