Disulfidptosis is a recently discovered form of regulated cell death, identified in 2023. This process involves a unique biochemical pathway, currently an area of active investigation to understand its implications.
Understanding Disulfidptosis
Disulfidptosis is characterized by the collapse of cytoskeleton proteins and F-actin due to an excessive buildup of disulfide bonds inside cells, known as “disulfide stress.” This stress triggers cell death by disrupting protein structures through abnormal disulfide linkages.
It is particularly observed in cells with high expression of solute carrier family 7 member 11 (SLC7A11) when deprived of glucose. Under these conditions, the cell’s redox balance is compromised, leading to abnormal disulfide bond formation and protein aggregation.
The Cellular Process
Disulfidptosis initiates from an imbalance in cysteine metabolism under glucose starvation. Cells with high SLC7A11, which imports cystine, take in excessive amounts. Without sufficient glucose, the cell cannot produce enough nicotinamide adenine dinucleotide phosphate (NADPH).
NADPH is important for converting cystine into cysteine. When NADPH is depleted, excess cystine accumulates, forming aberrant disulfide bonds within proteins. This disulfide stress primarily affects actin filaments, leading to their abnormal aggregation and cytoskeletal collapse.
This cytoskeletal breakdown, particularly of F-actin, is a key feature of disulfidptosis, resulting in loss of cell shape and integrity. Inhibiting glucose uptake with glucose transporter (GLUT) inhibitors can also trigger this process in SLC7A11-overexpressing tumor cells.
Distinguishing Disulfidptosis
Disulfidptosis differs from other regulated cell death forms like apoptosis, necrosis, and ferroptosis due to its unique triggers and mechanisms. Apoptosis, or programmed cell death, involves cell shrinkage, membrane blebbing, and DNA fragmentation.
Necrosis is a non-programmed cell death caused by severe injury, leading to cell swelling, membrane rupture, and release of cellular contents. Ferroptosis is an iron-dependent cell death characterized by toxic lipid reactive oxygen species (ROS) and lipid peroxidation. While both involve oxidative stress, ferroptosis targets lipids, whereas disulfidptosis focuses on protein misfolding and aggregation from disulfide bond imbalances and cytoskeletal collapse.
Disulfidptosis is distinct, primarily driven by disulfide stress and actin cytoskeleton collapse, a mechanism not central to these other pathways. Inhibitors of apoptosis, necroptosis, or ferroptosis do not prevent disulfidptosis.
Implications for Health and Disease
Understanding disulfidptosis has implications for various health conditions, particularly cancer. Many cancer cells exhibit altered metabolism, relying heavily on glucose and expressing high SLC7A11, making them susceptible to disulfidptosis under glucose deprivation. This vulnerability presents a potential avenue for cancer therapy.
Inducing disulfidptosis in tumor cells offers new strategies to combat cancer. Glucose transporter inhibitors, for example, can trigger disulfidptosis in SLC7A11-high cancer cells. This approach exploits the metabolic weaknesses of cancer cells, potentially leading to treatments with fewer side effects on healthy cells.
Beyond cancer, emerging research suggests a possible role for disulfidptosis in neurodegenerative diseases. Oxidative stress, including disulfide stress, is a hypothesized mechanism in central nervous system diseases like Alzheimer’s and Parkinson’s. Proteins and metabolic pathways involved in disulfidptosis are associated with these disorders.
Future Research and Therapeutic Avenues
Current research explores disulfidptosis as a therapeutic target, particularly in oncology. Scientists are investigating how to modulate this pathway to induce cancer cell death while sparing healthy tissues. Strategies include interrupting cellular energy supply and reducing power, such as integrating copper single-atom nanozymes and glucose oxidase to deplete NADPH and trigger disulfidptosis.
Challenges remain in optimizing drug bioavailability and elucidating molecular mechanisms to translate findings into clinical applications. The goal is to design antitumor agents that specifically induce disulfidptosis, potentially offering more effective and precise treatments.