Ferritin Light Chain: A Key Regulator of Nrf2-Dependent Ferroptosis in Oral Squamous Cell Carcinoma.

The m6A Reader IGF2BP2 Suppresses Ferroptosis in Nasopharyngeal Carcinoma by Stabilizing NRF2 mRNA.

Homocysteine promotes ferroptosis through NCOA4-mediated ferritinophagy in THP-1 macrophages

Introduction As an independent risk factor for atherosclerosis (AS), hyperhomocysteinemia (HHcy) exerts its pathogenic effects primarily through the induction of macrophage ferroptosis. As a selective autophagic process mediated by nuclear receptor coactivator 4 (NCOA4), ferritinophagy directly influences ferroptosis via its regulation of cellular iron balance. However, whether homocysteine (Hcy) regulates macrophage ferroptosis through ferritinophagy remains unclear. Methods Human acute monocytic leukemia (THP-1) cells were differentiated into macrophages and subsequently treated with Hcy. Ferroptosis was assessed by measuring glutathione (GSH) levels, reactive oxygen species (ROS), Fe²⁺ content, and mitochondrial morphology. Protein expression of NCOA4, FTH1, and GPX4 was examined, and GPX4 methylation was evaluated. The involvement of ferritinophagy was further verified using the ferroptosis inhibitor ferrostatin‑1 (Fer‑1) and the inducer Erastin. Activation of the IL‑6/STAT3 signaling pathway was also examined, along with its reciprocal regulation with ferroptosis. Results Hcy treatment promoted ferroptosis in THP‑1 macrophages, as indicated by decreased GSH levels, increased ROS and Fe²⁺ levels, and characteristic mitochondrial morphological changes. Hcy also enhanced GPX4 methylation, resulting in reduced GPX4 expression. Mechanistically, Hcy upregulated NCOA4 and downregulated FTH1, suggesting activation of NCOA4‑mediated ferritinophagy; these effects were reversed by Fer‑1 and augmented by Erastin. In addition, Hcy activated the IL‑6/STAT3 pathway, and its crosstalk with ferroptosis was confirmed by the reciprocal modulation with Fer‑1 and Erastin. Discussion Collectively, our study indicates that Hcy promotes ferroptosis in THP-1 macrophages through NCOA4-mediated ferritinophagy, and the IL-6/STAT3 signaling pathway plays a key role in this process. Therefore, targeting Hcy may represent a potential treatment strategy for AS.

GPR39 Suppresses Ferroptosis via the Nrf2/SLC7A11 Axis and Reduces the Sensitivity of Colorectal Cancer to Anti‐PD‐1 Immunotherapy

Background PD‐1 blockade has yet to achieve broad clinical success in colorectal cancer (CRC), with microsatellite‐stable tumors proving especially resistant. At the same time, ferroptosis has emerged as a mechanistic link between redox control in tumor cells and the antitumor immune response. GPR39 is overexpressed in CRC, but its functional role in ferroptosis and immunotherapy resistance is currently unclear. Methods GPR39 expression was analyzed in human and mouse CRC cell lines. GPR39 knockdown, with or without the ferroptosis inhibitor liproxstatin‐1, was performed to determine whether GPR39 regulates CRC cell proliferation and migration through ferroptosis. Ferroptosis was evaluated by measuring lipid peroxidation, glutathione (GSH) levels, ferrous iron (Fe2+) accumulation, and reactive oxygen species (ROS). Mechanistic involvement of the nuclear factor erythroid 2–related factor 2 (Nrf2)/solute carrier family 7 member 11 (SLC7A11) signaling axis was examined using Nrf2 overexpression. Subcutaneous implantation of MC38 cells with stable GPR39 knockdown was performed to evaluate whether GPR39 regulates tumor sensitivity to anti‐PD‐1 treatment in vivo in a ferroptosis‐dependent manner. Results GPR39 was markedly upregulated in CRC cell lines. GPR39 knockdown induced ferroptosis, characterized by increased lipid peroxidation, Fe2+ accumulation, and oxidative stress and accompanied by suppression of the Nrf2/SLC7A11 pathway. Nrf2 overexpression reversed these changes. Functionally, silencing GPR39 inhibited the proliferative and migratory capacities of CRC cells, effects that were largely rescued by liproxstatin‐1. In vivo, GPR39 knockdown significantly potentiated the antitumor activity of PD‐1 blockade, as evidenced by suppressed tumor progression accompanied by enhanced infiltration of CD8+ T cells, whereas ferroptosis inhibition abrogated these effects. Conclusion GPR39 suppresses ferroptosis in CRC via the Nrf2/SLC7A11 axis, thereby limiting PD‐1 immunotherapy efficacy.

GTP-binding protein DIRAS2 inhibits ferroptosis in oral leukoplakia via regulating iron metabolism.

BACKGROUND Oral leukoplakia (OLK) is the most prevalent and extensively studied oral potential malignant disorder (OPMD), with a high risk of progression to malignancy. Ferroptosis has been implicated as a key process in the progression of OLK, and iron metabolism significantly influences the ferroptosis process. DIRAS2, a member of the GTPase family within RAS proteins, is associated with ferroptosis, however, how DIRAS2 affects iron metabolism remains unknown. METHODS Immunohistochemical staining was used to assess the expression of SLC7A11 and LCN2 in human normal oral mucosa and OLK tissues. Erastin-induced Leuk-1 cells were employed to investigate ferroptosis through CCK8 assays, MDA and Fe²⁺ measurements, and alterations in mitochondrial membrane potential and morphology. qRT-PCR and western blotting were performed to detect the expression of iron metabolism-related molecules, additionally, LCN2 inhibitor and small interfering RNAs were employed in this study. Dual-luciferase assays, co-ip, CHX chase assay and Duolink assay were conducted to elucidate the interactions among DIRAS2, HIF1α, and LCN2. The findings were validated in 4-Nitroquinoline-1-oxide (4NQO) -induced mouse OLK models too. RESULTS SLC7A11 and LCN2 expression was upregulated in OLK specimens compared to normal oral mucosa tissues. DIRAS2 knockdown in Erastin-induced Leuk-1 cells exacerbated mitochondrial morphology alteration, increased MDA and Fe²⁺ levels, and further upregulated LCN2 and NCOA4 expression while decreasing FTH1 protein expression. Knockdown of LCN2 expression by inhibitor or small interfering RNAs decreased Fe²⁺ levels and related protein expression in Leuk-1 cells. Compared with normal tongue tissues, the expression of ACSL4, SLC7A11, and the LCN2-NCOA4/FTH1 pathway was elevated in 4NQO-induced mouse tongue tissues. Conditional knockout of DIRAS2 resulted in decreased expression of SLC7A11 and FTH1, while increased expression of ACSL4, LCN2, and NCOA4. Furthermore, DIRAS2 regulated the expression of LCN2 via HIF1α mediation. CONCLUSIONS DIRAS2 may regulate iron metabolism in ferroptosis during the progression of OLK.

DANGER/ITPRIP-Mediated Iron Homeostasis Mediates Ferroptosis Resistance and Presents a Potential Therapeutic Target in ccRCC.

Clear cell renal cell carcinoma (ccRCC) exhibits unique metabolic reprogramming characterized by disrupted iron homeostasis, primarily due to inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. This iron dysregulation creates a therapeutic opportunity through ferroptosis, an iron-dependent form of regulated cell death. However, the specific mechanisms enabling ccRCC cells to evade ferroptosis in high-iron microenvironments remain poorly understood, limiting targeted therapy development. In this study, we identified DANGER (inositol 1,4,5-trisphosphate receptor interacting protein, ITPRIP) as an oncoprotein specifically overexpressed in ccRCC. DANGER establishes a cytoprotective axis by promoting nuclear factor erythroid 2-related factor 2 (NRF2) nuclear translocation, leading to ferritin heavy chain 1 (FTH1) upregulation. The DANGER/NRF2/FTH1 signaling cascade enhances iron storage, reduces cytotoxic labile iron pools, and suppresses lethal lipid peroxidation, conferring robust ferroptosis resistance. Under high-iron stress, ccRCC cells collectively upregulate the pro-ferroptotic enzyme 5-lipoxygenase (ALOX5) alongside this protective axis, creating a ferroptosis pre-conditioning state that elevates the ferroptosis initiation threshold. Translationally, we discovered that deferasirox (DFX), a clinically approved iron chelator, functions as a direct DANGER inhibitor that disrupts this protective axis, resensitizes cells to ferroptosis, and suppresses tumor proliferation and migration. This work establishes DANGER-mediated iron homeostasis as a core mechanism of ferroptosis resistance in ccRCC and validates DFX as a mechanistically grounded therapeutic strategy.

ATF4/SCO2 Inhibits Ferroptosis in Lung Cancer Through Activating the MAPK Signaling Pathway

Ferroptosis is a specific cell death form resulting from the iron‐dependent lipid peroxidation, exhibiting an essential role in cancer progression. The purpose of this study was to explore the underlying mechanism of ferroptosis in lung cancer. The mRNA and protein expression levels were examined via real‐time quantitative PCR and Western blotting. Cell malignant behaviors were assessed using cell counting kit‐8 (CCK‐8) assay, transwell assay, and flow cytometry. Ferroptosis was determined using the indicators lipid reactive oxygen species (ROS), glutathione (GSH), and Fe2+. Dual‐luciferase reporter assay and chromatin immunoprecipitation assay were performed for binding analysis between activating transcription factor 4 (ATF4) and synthesis of cytochrome c oxidase 2 (SCO2). Associated proteins in mitogen‐activated protein kinases (MAPK) signaling pathway were measured by Western blotting. A mouse model was established by implanting lung cancer cells for in vivo research. Lung cancer samples and cells exhibited high expression of SCO2. SCO2 downregulation restrained lung cancer cell growth by inducing ferroptosis. ATF4 was an up‐regulated gene in lung cancer, and it elevated SCO2 expression by binding to the promoter of SCO2. ATF4 knockdown repressed cell proliferation and migration while facilitating apoptosis and ferroptosis by down‐regulating SCO2. Inhibition of ATF4/SCO2 inactivated the MAPK signaling pathway. ATF4‐mediated SCO2 promoted lung tumorigenesis in vivo. This study manifested that ATF4 controlled SCO2 to suppress ferroptosis by activating the MAPK pathway, thus contributing to lung cancer development.