Ovarian cancer remains difficult to treat due to the persistence of chemoresistant cancer stem-like cells (CSCs), which are major drivers of tumor relapse. Herein, we engineered a hyaluronic acid-functionalized nanoplatform (HS-Cu@DOX) via the assembly of a shikonin–copper (SKN-Cu) coordination complex with hyaluronic acid, followed by electrostatic loading of doxorubicin (DOX), enabling tumor-targeted co-delivery of both therapeutic agents. This nanoplatform disrupts intracellular redox homeostasis to induce cuproptosis while concurrently suppressing CSC stemness through downregulation of key pluripotency-associated transcription factors (e.g., SOX2, OCT4, and NANOG). By depleting intracellular glutathione (GSH) and impairing antioxidant defenses, HS-Cu@DOX disrupts the oxidative stress resilience of CSCs, thereby restoring their sensitivity to DOX-induced apoptosis. Consequently, this strategy enhances DOX-mediated cytotoxicity and reduces systemic toxicity while maintaining potent antitumor efficacy. Collectively, our findings demonstrate that combining cuproptosis induction with CSC stemness suppression represents a promising strategy for overcoming chemoresistance, highlighting HS-Cu@DOX as a potential therapeutic candidate for recurrent ovarian cancer.
Shanshan Liu, Yichun Huang, Fanchen Yan et al.· Materials Today Bio· 0 citations
Liver cancer, a prevalent and aggressive malignancy globally, is associated with high morbidity and mortality rates. Butyrate, a metabolite produced by intestinal microbiota, is capable of restricting cancer initiation and progression. However, the precise mechanisms underlying its effects on liver cancer remain poorly understood. This study utilized a CCK-8 cytotoxicity assay to demonstrate that sodium butyrate (NaB) suppresses liver cancer cell proliferation through ferroptosis and apoptosis. The involvement of ATF4/SLC7A11 signaling and mitochondrial dysfunction in NaB-induced ferroptosis and apoptosis was further investigated. Results revealed a decrease in ATF4 and SLC7A11 expression, an elevation in the levels of malondialdehyde (MDA) and reactive oxygen species (ROS), and a reduction in glutathione (GSH) in NaB-treated liver cancer cells. These ferroptosis-related alterations could be reversed by an ATF4 activator. Additionally, NaB-treated liver cancer cells presented a decrease in mitochondrial membrane potential (MMP), accumulation of mitochondrial ROS, and mitochondrial damage. These cellular changes disrupted the BAX/BCL-2 balance, leading to cytochrome C release, which subsequently activated caspase9 and caspase3, initiating mitochondrial pathway apoptosis. In vivo, NaB treatment resulted in increased iron content in liver cancer tissues, along with upregulated cytochrome C, activated caspase9, and caspase3 expression; these effects were counteracted by ferrostatin-1 (Fer-1). Collectively, this study elucidates that NaB induces mitochondrial damage via ferroptosis mediated by ATF4/SLC7A11, ultimately triggering mitochondrial pathway apoptosis in hepatoma cells. These findings may offer novel insights into therapeutic strategies for hepatoma.
Xiaolan Meng, Yubin Li, Miao He et al.· PLoS ONE· 0 citations
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