Researchers have identified a potential new strategy to limit the spread of breast cancer to the lungs by targeting the metabolic processes that help cancer cells survive and grow. The study, published in Cancer Biology & Medicine in March 2026, suggests that mitochondrial uncouplers could suppress a key metabolic pathway used by cancer cells and significantly reduce lung metastasis in mouse models. The findings offer a promising direction for developing future treatments for metastatic breast cancer, although further research is needed before the approach can be tested for clinical effectiveness in humans.
The research was conducted by scientists at Stanford University School of Medicine, in collaboration with researchers at The Second Hospital of Jilin University and Agilent Technologies. Led by Jiangbin Ye, the team investigated how mitochondrial uncouplers, including niclosamide ethanolamine (NEN) and BAM15, affect mitochondrial function and serine metabolism in cancer cells. The researchers focused on the mitochondrial serine catabolic pathway (MSCP), also known as serine, glycine and one-carbon metabolism, which supports cancer cell growth by supplying essential metabolic building blocks and maintaining cellular balance.
The MSCP pathway plays an important role in cancer progression because it helps cells produce amino acids, components needed for DNA synthesis, and molecules that protect against oxidative stress. Two key enzymes in this pathway, serine hydroxymethyltransferase 2 (SHMT2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), are frequently overexpressed in human cancers. Their activity can support tumor growth and metastatic spread, making the pathway an attractive target for potential cancer therapies.
To investigate the pathway, researchers used uniformly carbon-13-labeled serine to trace how cancer cells process the amino acid. They found that treatment with NEN and BAM15 did not significantly change serine uptake, but sharply reduced the incorporation of serine-derived carbon into glycine and purine nucleotides. This indicated that the drugs disrupted the flow of serine through the metabolic pathway and reduced the cells’ ability to produce important components required for DNA and RNA synthesis.
The researchers also found that mitochondrial uncouplers increased oxygen consumption and the ratio of NAD+ to NADH, indicating enhanced mitochondrial respiration and a reduction in reductive stress. With prolonged treatment, the drugs lowered the levels of several mitochondrial metabolic enzymes, including SHMT2, MTHFD2 and MTHFD1L, in triple-negative breast cancer and pancreatic cancer cells. In contrast, levels of the related cytosolic enzyme SHMT1 remained largely unaffected, suggesting that the treatment selectively altered mitochondrial serine metabolism.
A key finding involved fat mass and obesity-associated protein (FTO), an enzyme that regulates chemical modifications on RNA molecules. The researchers observed that mitochondrial uncoupling reduced levels of 2-hydroxyglutarate (2-HG), a metabolite that can inhibit FTO, alongside a reduction in global N6-methyladenosine (m6A) RNA modifications. FTO helps remove these modifications from RNA, and its activity may influence the expression of genes involved in cancer metabolism.
Further experiments supported the proposed mechanism. Inhibiting FTO, either pharmacologically or genetically, restored the expression of several MSCP enzymes. Supplementing cells with L-2-HG increased m6A levels and MSCP enzyme expression, whereas adding alpha-ketoglutarate reduced them. These results suggest that mitochondrial uncouplers may restore FTO activity by lowering 2-HG, thereby changing RNA modifications that regulate the production of enzymes supporting cancer cell metabolism.
The team then evaluated the effects of NEN in mice. Animals receiving a diet containing 2,000 parts per million of NEN showed a significant reduction in breast cancer metastasis to the lungs. The researchers also found that low FTO expression was associated with poorer relapse-free survival among breast cancer patients, while SHMT2 was overexpressed in metastatic samples. These observations support the potential importance of the metabolic pathway in cancer progression, although the patient findings establish associations rather than proof that changing FTO activity will improve survival.
According to the researchers, the findings offer a new perspective on the Warburg effect, the tendency of many cancer cells to rely heavily on glucose metabolism even when oxygen is available. Their work suggests that restoring mitochondrial respiratory activity could expose metabolic vulnerabilities that cancer cells use to survive under stressful conditions. By connecting mitochondrial function, RNA regulation and metastatic behavior, the study identifies a potential therapeutic pathway for further investigation.
Despite the encouraging results, mitochondrial uncouplers are not yet established treatments for metastatic breast cancer. Niclosamide, the parent compound of NEN, is approved as an antiparasitic medication, but its effectiveness in cancer treatment has been limited, potentially because of poor bioavailability and safety-related dosing constraints. BAM15 and newer mitochondrial uncouplers may offer alternative research candidates, but their safety, appropriate dosing and effectiveness in humans remain to be established.
The researchers emphasized the need for further studies to determine whether these compounds can safely suppress cancer metabolism in patients and whether combining mitochondrial uncoupling with existing cancer treatments could improve outcomes or delay metastatic progression. If validated in future research, this strategy could provide a new way to target the metabolic adaptations that help breast cancer spread beyond its original site.
