H<sub>2</sub>S-scavenging bimetallic phenolic network induces metabolic reprogramming to sensitize colorectal cancer to cuproptosis and ferroptosis.
basic_science · Level V
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- Record sourced from PubMed, PMID 42731546.
- Also identified by DOI 10.1016/j.biomaterials.2026.124616.
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Abstract
Colorectal cancer (CRC) treatment is severely hindered by the hydrogen sulfide (H<sub>2</sub>S)-rich microenvironment and metabolic dysregulation, characterized by the Warburg effect and high glutathione (GSH) concentrations. Herein, we engineer a bimetallic phenolic nanoplatform (ZCTDFe, loaded with doxorubicin) to scavenge endogenous H<sub>2</sub>S and induce metabolic reprogramming, sensitizing tumors to cuproptosis- and ferroptosis-associated processes while integrating photothermal therapy (PTT) and chemotherapy. Through an "etching-coordination" strategy, ZCTDFe effectively scavenged H<sub>2</sub>S (75.2%) and promoted CuS formation under sulfide-rich cell-free conditions, while intracellular TEM-EDS analysis revealed Cu-S-containing deposits consistent with the scavenging reaction. Seahorse extracellular flux analysis revealed a biphasic bioenergetic response characterized by an early reduction in glycolytic activity accompanied by increased mitochondrial respiratory engagement, followed by later impairment of mitochondrial respiration and glycolytic function. This early respiratory engagement may increase cellular susceptibility to copper-dependent proteotoxic stress involving lipoylated TCA-associated proteins. These metabolic and molecular changes were accompanied by abnormal DLAT oligomerization and loss of Fe-S cluster proteins, supporting the involvement of cuproptosis-associated proteotoxic stress. Meanwhile, the bimetallic center initiates Fenton-like reactions and enhances GSH depletion, thereby weakening the GSH/GPX4 antioxidant defense and promoting ferroptosis-associated lipid peroxidation. Pharmacological rescue experiments supported a synergistic interaction between cuproptosis- and ferroptosis-associated processes within the overall multimodal cytotoxic response. In vitro and in vivo evaluations confirmed its potent antitumor efficacy. The nanoplatform achieved marked tumor growth inhibition in the CRC model without overt systemic toxicity during the short-term observation period.