Attenuated growth factor signaling during cell death initiation sensitizes membranes towards peroxidation

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 25, 2025

Abstract Cell death programs such as apoptosis and ferroptosis are associated with aberrant redox homeostasis linked to lipid metabolism membrane function. Evidence for cross-talk between these is emerging. Here, we show that cytotoxic stress channels polyunsaturated fatty acids via lysophospholipid acyltransferase 12 into phospholipids become susceptible peroxidation under additional stress. This reprogramming altered acyl-CoA synthetase isoenzyme expression caused by a decrease in growth factor receptor tyrosine kinase (RTK)-phosphatidylinositol-3-kinase signaling, resulting suppressed acid biosynthesis, specific stressors impaired Akt-SREBP1 activation. The reduced availability of de novo synthesized favors the channeling phospholipids. Growth withdrawal serum starvation mimics this phenotype, whereas RTK ligands counteract it. We conclude attenuated signaling during cell initiation increases cells’ susceptibility oxidative damage at interface alternative programs.

Язык: Английский

Iron-Dependent Cell Death: Exploring Ferroptosis as a Unique Target in Triple-Negative Breast Cancer Management

Cancer Management and Research, Год журнала: 2025, Номер Volume 17, С. 625 - 637

Опубликована: Март 1, 2025

Triple-negative breast cancer (TNBC) is characterized by aggressive behavior, high metastatic potential, and frequent relapses, presenting significant treatment challenges. Ferroptosis, a unique form of programmed cell death marked iron-dependent lipid peroxidation, has emerged as crucial factor in biology. Recent studies indicate that TNBC cells possess distinct metabolic profile linked to iron glutathione, which may render them more susceptible ferroptosis than other subtypes. Moreover, plays role the interactions between immune tumor cells, suggesting its potential modulate microenvironment influence response against TNBC.Evidence reveals not only affects viability but also alters promoting release damage-associated molecular patterns (DAMPs), can recruit site. Specific ferroptosis-related genes biomarkers, such ACSL4 GPX4, demonstrate altered expression tissues, offering promising avenues for diagnostic prognostic applications. Furthermore, preclinical models, induction been shown enhance efficacy existing therapies, indicating synergistic effect could be harnessed therapeutic benefit. The compelling link underscores novel target. Future research should focus on developing strategies exploit conjunction with traditional including identification natural compounds efficacious inducers personalized regimens. This review elucidates multifaceted implications TNBC, providing valuable insights improving both diagnosis this formidable subtype.

Язык: Английский

A Novel Nanomedicine for Osteosarcoma Treatment: Triggering Ferroptosis through GSH Depletion and Inhibition for Enhanced Synergistic PDT/PTT Therapy

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Дек. 2, 2024

Osteosarcoma treatment remains challenging due to the limitations of single-modality therapies.To address this, we designed a carrier-free nanomedicine [email protected]@IR780 (CSIR) for synergistic ferroptosis, photodynamic therapy (PDT), and photothermal (PTT) in osteosarcoma. Interestingly, CSIR could harness enhanced permeability retention (EPR) effect effectively enter tumors. Copper ions (Cu²⁺) within react with reductive intracellular environment, depleting glutathione (GSH) levels. Near-infrared (NIR) irradiation further depleted GSH through reactive oxygen species (ROS) generation. Additionally, released sorafenib (SRF), which inhibited cystine-glutamate antiporter system xCT (xCT), thereby blocking biosynthesis. RNA sequencing data confirmed ferroptosis induction by CSIR. This strategy depletion-induced PDT, cascade holds promise improved osteosarcoma future design.

Язык: Английский