The discovery of a cellular process called disulfidptosis is opening new doors in the fight against stomach cancer.
Gastric cancer remains one of the most challenging cancers to treat, with a five-year survival rate of only 32% despite advances in medical science. The complexity of this disease drives researchers to constantly search for new approaches to improve patient outcomes.
In 2023, a groundbreaking discovery emerged—a previously unknown form of programmed cell death called disulfidptosis. This cellular process, triggered by disulfide stress within cells, has opened an exciting new frontier in cancer research. At the center of this story is a mitochondrial protein called NUBPL, whose unexpected role in gastric cancer progression is reshaping our understanding of the disease and pointing toward novel treatment strategies.
Disulfidptosis represents a distinct form of cellular death that differs fundamentally from other known processes like apoptosis, necrosis, autophagy, and ferroptosis. This mechanism was first proposed in 2023 by Professor Gan's team at MD Anderson Cancer Center in the United States 5 .
The process occurs when cancer cells experience glucose deprivation. Under these conditions, cells with high expression of a protein called SLC7A11 excessively absorb cystine, leading to depletion of NADPH—a crucial molecule for maintaining cellular redox balance. This depletion prevents the conversion of cystine to cysteine and triggers disulfide stress, causing abnormal disulfide bonds to form in actin cytoskeletal proteins. The result is the collapse of the cell's structural framework and ultimately, cellular demise 2 5 .
The NUBPL protein, officially named "Nucleotide Binding Protein Like," is not new to science, but its role in cancer represents a surprising career shift. Under normal circumstances, NUBPL serves as an essential assembly factor for mitochondrial complex I, the main entry point to the mitochondrial respiratory chain. It plays a critical role in transferring iron-sulfur clusters into complex I subunits, making it vital for cellular energy production 9 .
Complex I assembly factor
Mitochondrial disorders
Gastric cancer progression
Disulfidptosis regulation
NUBPL's connection to human disease was first established through its link to mitochondrial disorders. Research has shown that mutations in the NUBPL gene can cause mitochondrial complex I deficiency, resulting in severe neurological problems including seizures, intellectual disability, and ataxia associated with cerebellar hypoplasia 6 8 .
The protein's involvement in cancer, particularly gastric cancer, represents a fascinating new dimension to its biological portfolio—one that researchers are just beginning to understand.
In a comprehensive study published in 2025, researchers embarked on an ambitious project to identify genes linked to disulfidptosis in gastric cancer 1 2 5 . They began by collecting gastric cancer transcriptomic data from The Cancer Genome Atlas (TCGA) database, including 383 tumor samples and 36 adjacent normal tissues. Through an extensive literature review, they identified 29 genes potentially associated with disulfide stress 2 5 .
Gathered transcriptomic data from TCGA database (383 tumor samples, 36 normal tissues)
Identified 29 genes potentially associated with disulfide stress
Applied multiple algorithms to identify key predictors
Conducted in vitro experiments to confirm biological function
The research team then employed multiple machine learning algorithms to sift through these genes and identify the most promising predictors for gastric cancer. This sophisticated approach included:
| Method | Key Parameters | Primary Function |
|---|---|---|
| LASSO Regression | k=10 fold cross-validation | Variable selection and regularization |
| Random Forest | ntree=1000, nodesize=50 | Feature importance ranking |
| Boruta Algorithm | Comparison with shadow features | Stepwise feature screening |
| SVM-RFE | 10-fold cross-validation | Feature elimination and ranking |
| XGBoost | max depth=6, learning rate=0.5 | Model training and feature evaluation |
After computational methods consistently highlighted NUBPL as a key candidate, the team turned to laboratory experiments to validate its biological function. They conducted in vitro experiments using gastric cancer cell lines to investigate how NUBPL influences cancer cell behavior 1 .
Invasion and migration of cancer cells
Cell proliferation and apoptosis
The results revealed a surprising finding: NUBPL affected the invasion and migration of gastric cancer cells rather than their proliferation and apoptosis. This suggested that NUBPL might play a specialized role in cancer metastasis rather than initial tumor growth 1 .
Further investigation revealed the mechanism behind this observation: NUBPL regulates the pentose phosphate pathway (PPP) and inhibits disulfidptosis. The PPP plays a crucial role in maintaining cellular antioxidant defense by providing NADPH, which helps recycle oxidized glutathione into reduced glutathione, thereby protecting cells from oxidative damage 1 5 .
| Experimental Focus | Key Finding | Biological Significance |
|---|---|---|
| Cancer cell invasion and migration | Significantly affected by NUBPL | Suggests role in metastasis rather than initial tumor growth |
| Cell proliferation and apoptosis | Not significantly affected by NUBPL | Indicates specialized function distinct from common cancer pathways |
| Pentose Phosphate Pathway (PPP) | Regulated by NUBPL | Connects NUBPL to cellular antioxidant defense and redox balance |
| Disulfidptosis | Inhibited by NUBPL | Positions NUBPL as regulator of novel cell death pathway |
The clinical implications of NUBPL expression in gastric cancer patients proved to be significant. Researchers found that aberrant NUBPL expression strongly impacts patient prognosis and modulates both metabolic and immune-related pathways 1 .
These findings position NUBPL as not only a prognostic biomarker but also a potential modulator of the tumor immune microenvironment.
The discovery of NUBPL's role in gastric cancer opened exciting possibilities for targeted therapies. Researchers utilized the Genomics of Drug Sensitivity in Cancer (GDSC) database to identify potential inhibitors that might target NUBPL function 1 2 .
Inhibits protein-protein interactions
Research compoundTyrosine kinase inhibitor
Approved drugJNK inhibitor
Experimental| Compound | Known Mechanism | Current Status | Potential Application |
|---|---|---|---|
| QS11 | Inhibits protein-protein interactions | Research compound | Potential NUBPL pathway inhibition |
| Imatinib | Tyrosine kinase inhibitor | Approved for other cancers | Repurposing opportunity for gastric cancer |
| AS601245 | JNK inhibitor | Experimental compound | Possible dual pathway targeting |
These findings suggest that targeting NUBPL could represent a viable strategy for developing new gastric cancer treatments, particularly for patients with elevated NUBPL expression.
Advancing NUBPL research requires specialized laboratory tools. Fortunately, several key reagents are available to scientists exploring this protein:
Essential for detecting NUBPL protein levels in tissue samples through techniques like Western blotting and immunohistochemistry 4
Full-length human NUBPL clone (NCBI Ref Seq: NM_001201573.1) enables gene expression studies and functional characterization 9
Used to knock down NUBPL expression in cell lines, allowing researchers to study the functional consequences of reduced NUBPL levels 1
These research tools have been instrumental in uncovering NUBPL's role in gastric cancer and continue to support ongoing investigations.
The discovery of NUBPL's involvement in gastric cancer represents a compelling example of how basic cellular processes can reveal unexpected insights into disease mechanisms. Once known only for its role in mitochondrial function, NUBPL has emerged as a key player in disulfidptosis regulation with significant implications for gastric cancer progression and treatment.
The multidisciplinary approach that uncovered NUBPL's importance—combining bioinformatics, machine learning, and molecular biology—showcases the power of integrated methodologies in modern cancer research. As scientists continue to unravel the complexities of disulfidptosis and NUBPL's role within this pathway, we move closer to personalized treatment strategies that could improve outcomes for gastric cancer patients.
The journey from discovering a fundamental cellular process to identifying potential therapeutic targets demonstrates how basic scientific research continues to drive clinical innovation, offering hope in the ongoing battle against gastric cancer.