Mitochondrial SLC25A46 Rewires Fatty Acid Oxidation to Promote Cell Proliferation and Ferroptosis Evasion in Ovarian Cancer by Stabilizing CACT

MCAT-mediated mitochondrial fatty acid metabolism regulates Lauren subtype divergence and suppresses gastric cancer progression through ROS/P53-dependent mitophagy and ferroptosis.

METTL7A Downregulation Drives SLC1A5‐Mediated Glutamine Competition to Promote Tumor Proliferation and Suppress CD8+ T Cell Immunity in Gastric Cancer

ABSTRACT Tumor metabolic dysregulation is a critical determinant of tumor progression and response to immunotherapy. Aberrant glutamine metabolism is a hallmark of gastric cancer (GC). However, beyond fueling GC cell anabolism, its role in remodeling the immunosuppressive tumor microenvironment remains poorly understood. Here, we show that GC cells overexpress solute carrier family 1 member 5 (SLC1A5) to drive glutamine accumulation, which not only promotes their own proliferation but also reduces glutamine availability to CD8+ T cells, thereby suppressing antitumor immunity. These dual effects cooperatively drive GC progression. Mechanistically, loss of methyltransferase‐like protein 7A (METTL7A) stabilizes SLC1A5 mRNA by reducing its m6A modification. Concurrently, METTL7A deficiency increased N‐glycosyltransferase β‐1,4‐galactosyltransferase 5 (B4GALT5) expression. B4GALT5 stabilizes SLC1A5 via N‐glycosylation at the N212 site, which blocks K48‐linked polyubiquitination and proteasomal degradation. We identify the natural flavonoid luteolin as an agent that upregulates METTL7A expression, which subsequently downregulates SLC1A5 expression and inhibits GC progression. Furthermore, luteolin significantly enhances the efficacy of anti‐PD‐1 therapy in GC. Collectively, our findings reveal that SLC1A5‐mediated glutamine competition drives both tumor cell proliferation and immune evasion in GC, and suggest that targeting the METTL7A/SLC1A5 axis may represent a promising therapeutic strategy.

CD276 promotes lipid metabolic reprogramming and regulates ferroptosis in clear cell renal cell carcinoma by upregulating FASN expression via SREBP1

Fatty acid-binding protein 2 suppresses liver metastasis by cytoplasmic sequestration of β-catenin to enhance ferroptosis sensitivity in colon cancer

Metastatic colon cancer commonly exhibits resistance to ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation. However, the mechanisms linking metabolic regulation to ferroptosis during metastatic progression remain incompletely understood. Here, we identified fatty acid-binding protein 2 (FABP2) as a regulator associated with ferroptosis sensitivity and liver metastatic phenotypes in colon cancer. Multi-omics analyses of clinical specimens showed reduced FABP2 expression in advanced colon cancer, which was associated with metastatic progression and poor survival. Mechanistically, FABP2 interacted with β-catenin, altered its intracellular localization, and was associated with reduced β-catenin/TCF4-dependent transcription of glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis resistance. FABP2 overexpression increased ferroptosis sensitivity, whereas FABP2 downregulation promoted GPX4-dependent ferroptosis evasion and metastatic phenotypes. Pharmacological inhibition of Wnt/β-catenin signaling or GPX4 activity partially attenuated the effects of FABP2 loss. Together, these findings identify FABP2 as a factor associated with ferroptosis regulation and metastatic progression in colon cancer, and provide additional insight into the interplay between lipid metabolism, Wnt/β-catenin signaling, and ferroptosis.

Peroxiredoxin 6 Silencing Remodels Lipid Metabolism and Redox Pathways to Promote Ferroptosis-Mediated Radiosensitization in Nonsmall Cell Lung Cancer

Ionizing radiation (IR) induces oxidative stress and lipid peroxidation with ferroptosis contributing to radiation-induced cancer cell death. Peroxiredoxin 6 (PRDX6), a multifunctional enzyme involved in phospholipid repair and redox regulation, has been implicated in ferroptosis regulation, but its role in the radiosensitivity of cancer cells remains unclear. Here, we show that PRDX6 depletion enhances radiosensitivity in A549 lung cancer cells. PRDX6-silenced A549 cells exhibited elevated lipid peroxidation and labile iron levels, indicating a ferroptosis-prone state that was amplified by radiation. To identify the underlying drivers of ferroptosis sensitivity in the PRDX6 background, we performed global proteomic profiling of PRDX6-silenced A549 cells, with and without radiation. Basal PRDX6-deficient cells displayed increased levels of ACSL4 and DHCR7. ACSL4 activates peroxidation-prone polyunsaturated fatty acids for incorporation into membrane phospholipids, and DHCR7 depletes the antiferroptotic moiety, 7-dehydrocholesterol. MPST, an antioxidant protein, was downregulated. These changes were accentuated upon IR exposure with further suppression of GINS4, a negative regulator of ferroptosis. Functional rescue by oleic acid suggested the role of ACSL4 in the observed phenotypes. Radiosensitization via ferroptosis induction was additionally demonstrated in another human lung cancer cell line under the PRDX6-silenced state. Collectively, PRDX6 loss remodels the cellular proteome to establish a presensitized redox and lipid compositional state, which favors ferroptosis-driven radiosensitivity.

Potential Mechanisms Underlying Ferroptosis-Associated NK Cell Dysfunction and Its Regulatory Networks in the Tumor Microenvironment

Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation. Its role in tumor immunity has attracted increasing attention in recent years. Natural killer (NK) cells are important antitumor immune effector cells, whereas metabolic reprogramming and oxidative stress in the tumor microenvironment (TME) may promote their functional exhaustion and ferroptotic cell death. This review summarizes the potential effects of cancer-associated fibroblasts (CAFs), the kynurenine metabolic pathway, and the tumor microenvironment itself on NK cell ferroptosis. Existing studies suggest that CAFs-induced NK cell ferroptosis can occur through dysregulated iron metabolism and ferritinophagy. In addition, the accumulation of kynurenine may further promote iron-dependent lipid peroxidation in NK cells. The amino acid transporter SLC7A5 may participate in this process by mediating kynurenine uptake, although direct evidence remains limited. Moreover, nutrient deprivation, lipid metabolic reprogramming, and redox imbalance in the TME may collectively increase the susceptibility of NK cells to ferroptosis. Ferroptosis of NK cells may be an important mechanism connecting tumor metabolic reprogramming and immune dysfunction, and is expected to become a new direction for immunotherapy intervention.