Disulfide-Bridged Ru Complex-Mediated Photo-Disulfidptosis for Colorectal Cancer Therapy

Area of Science:

• Biochemistry
• Oncology
• Materials Science

Background:

• Colorectal cancer (CRC) remains difficult to treat despite various therapeutic strategies.
• Disulfidptosis, a novel cell death pathway, involves NADPH depletion and disulfide bond formation, particularly in high SLC7A11-expressing cells under glucose starvation.
• CRC cells exhibit high SLC7A11 expression and a hypermetabolic phenotype, making disulfidptosis a potential therapeutic target.

Purpose of the Study:

• To develop a novel therapeutic strategy targeting disulfidptosis for colorectal cancer (CRC) treatment.
• To investigate the efficacy of a binuclear ruthenium complex (RuSSRu) in inducing disulfidptosis in CRC cells.

Main Methods:

• Development of a binuclear ruthenium complex, RuSSRu, bridged by a disulfide bond.
• Utilizing two-photon excitation to activate RuSSRu, generating reactive oxygen species (ROS) and inducing lysosomal damage.
• Analyzing metabolic disruptions, including disulfide bond accumulation and NADPH depletion, leading to cytoskeletal collapse and disulfidptosis.

Main Results:

• RuSSRu effectively induced disulfidptosis in CRC cells via ROS generation and lysosomal damage.
• The treatment triggered metabolic cascade: disulfide bond accumulation and NADPH depletion.
• Synergistic cell death was observed through the combined effects of disulfidptosis and lysosomal damage-induced apoptosis.

Conclusions:

• RuSSRu represents a novel therapeutic platform for CRC by effectively inducing disulfidptosis.
• The study unveils a new mechanism for CRC treatment involving synergistic cell death pathways.
• Targeting disulfidptosis offers a promising strategy for managing colorectal cancer.