Erastin

Osteoarthritis (OA) is a progressive joint disorder characterized by cartilage degradation and increased oxidative stress. Recently, OA pathogenesis has been related to ferroptosis, an iron-dependent programmed cell death associated with oxidative damage. However, its regulatory mechanisms remain unclear. We sought to clarify the involvement of Targeting Protein for Xklp2 (TPX2) in ferroptosis regulation and its interaction with the nuclear factor kappa-light-chain-enhancer of activated B cells p65 subunit (NF-κB p65) pathway in OA.

To mimic OA conditions in vitro, C28/I2 chondrocytes were incubated with 5 µg/mL Lipopolysaccharide (LPS) for a 24-hour period. Intracellular iron levels (Fe²⁺, Fe³⁺, total iron) were measured using colorimetric assays. Glutathione peroxidase (GSH-Px) activity and glutathione (GSH/GSSG) levels were determined. Mitochondrial morphology was examined by transmission electron microscopy. Key ferroptosis markers (Solute Carrier Family 7 Member 11, SLC7A11; Glutathione Peroxidase 4, GPX4) were analyzed at the mRNA and protein levels. Cellular responses were evaluated utilizing cell counting kit-8 (CCK-8) viability assays, 5-Ethynyl-2'-deoxyuridineb (EdU) proliferation staining, and flow cytometry.

LPS treatment significantly increased intracellular iron accumulation while decreasing GSH-Px activity and GSH/GSSG levels, accompanied by characteristic mitochondrial damage. TPX2 expression was significantly elevated in LPS-induced chondrocytes, whereas TPX2 knockdown reversed ferroptosis-related biochemical alterations and restored GPX4 and SLC7A11 expression via inhibition of NF-κB p65 phosphorylation. Moreover, NF-κB p65 overexpression attenuated these protective effects of TPX2 silencing. Ferroptosis activation by erastin abolished the protective effects conferred by TPX2 knockdown.

Our in vitro findings suggest that TPX2 may promote ferroptosis in LPS-induced C28/I2 chondrocytes via NF-κB p65 signaling, reducing antioxidant defenses. Further in vivo and clinical studies are needed to clarify its role and therapeutic potential in OA.

Bladder cancer ranks among the most common malignancies of the urinary system. Despite continuous advances in treatment technologies, the risk of tumor progression and metastasis remains high due to its extreme heterogeneity, resulting in poor patient prognosis. Patients with muscle-invasive bladder cancer face the greatest challenges. Immediate clinical treatment is radical cystectomy after the administration of neoadjuvant therapy. The effect of different conventional chemotherapeutic drugs is heavily impaired by tumor resistance. In turn, the research of effective therapeutic approaches to prevent resistance of malignant tumors has turned out to be the most important clinical concern in the management of bladder cancer. Ferroptosis is another type of programmed cell death that is morphologically and mechanistically different than apoptosis and necrosis. To maintain high rates of proliferation, bladder cancer cells are hypernormal to iron-dependent oxidative stress. So using the ferroptosis inducers to destabilize their vulnerable antioxidant defenses provides a very specific targeting approach to the weaknesses of this natural metabolic homeostasis. Inductors of ferroptosis (erastin, artemisinin, conjugated polymer nanoparticle, quinazoline-aromatic urea analogue derivatives, etc.) show great potential in improving the efficacy of traditional anticancer drugs used to fight against bladder cancer. Preclinical studies combining standard therapies with ferroptosis-related treatments have yielded promising results. However, clinical trials targeting ferroptosis in bladder cancer remain scarce, posing challenges for translating these findings into clinical practice. In this review, we aim to highlight the latest advances in ferroptosis induction as a therapeutic strategy for bladder cancer. It provides a reference for subsequent research and additional insights into the development and validation of corresponding drugs for bladder cancer treatment.