Stigmasterol suppresses glioblastoma growth through mitochondrial dysfunction and oxidative stress

Glioblastoma remains one of the most formidable challenges in clinical oncology. This aggressive primary brain tumor is characterized by rapid progression, extensive metabolic reprogramming, and devastatingly poor therapeutic outcomes, with median survival for patients typically measured in months despite surgery, radiation, and chemotherapy. Now, a new study published in BMC Cancer by Bolin Gao, Peng Yun, and Chen Liang of the Department of Neurosurgery at The First Affiliated Hospital of Xi’an Jiaotong University offers a fresh line of attack: a plant-derived sterol called stigmasterol that appears to sabotage the very metabolic machinery glioblastoma cells depend on to survive.

Stigmasterol is a phytosterol, a compound structurally similar to cholesterol that is found in vegetable oils, legumes, nuts, and seeds. It has previously demonstrated anti-tumor activity in several malignancies, but its effects on mitochondrial metabolism in glioblastoma had remained unclear. The new research, conducted in open-access form and funded by the Key Research and Development Plan of Shaanxi Province, China, set out to close that gap by combining preclinical tumor models, transcriptomic profiling, and detailed measurements of mitochondrial function.

The team evaluated tumor growth using a U87-MG xenograft model, in which human glioblastoma cells are implanted into experimental animals. Stigmasterol treatment significantly inhibited xenograft tumor growth, and in cell culture it reduced the clonogenic capacity of glioblastoma cells, meaning the cells lost their ability to form new colonies over the long term, a key indicator of proliferative potential. These results established that the compound has a genuine suppressive effect on glioblastoma growth, not merely a cytostatic hint.

To understand how stigmasterol exerts this effect, the researchers turned to the mitochondria, the organelles that serve as the power plants of the cell. In glioblastoma, mitochondrial function is often rewired to support the tumor’s voracious energy demands and its adaptation to hypoxic conditions within the brain. The team measured mitochondrial membrane potential, the electrical gradient across the inner mitochondrial membrane that drives ATP synthesis, and found that stigmasterol treatment decreased this potential, indicating impaired mitochondrial function.

The researchers also assessed the activity of complex I, the first and largest enzyme complex of the electron transport chain, which is responsible for transferring electrons from NADH to ubiquinone while pumping protons across the inner mitochondrial membrane. Stigmasterol reduced complex I activity, further compromising the electron transport chain. At the same time, the team observed increased accumulation of mitochondrial reactive oxygen species, or ROS, the chemically reactive molecules containing oxygen that can damage DNA, proteins, and lipids when produced in excess. Together, these findings indicate that stigmasterol induces both mitochondrial dysfunction and enhanced oxidative stress in glioblastoma cells.

To identify the molecular pathways affected by stigmasterol, the team performed transcriptomic analysis, comparing gene expression profiles between treated and untreated cells. This revealed coordinated alterations in metabolism-related genes. Two genes were downregulated: Aconitase 2, or ACO2, which encodes an enzyme of the tricarboxylic acid cycle responsible for converting citrate to isocitrate, and 3-hydroxyacyl-CoA dehydratase 2, or HACD2, which participates in fatty acid metabolism. Meanwhile, one gene was upregulated: NDUFA4L2, the NADH dehydrogenase ubiquinone 1 alpha subcomplex subunit 4-like 2, a protein known to modulate complex I activity and mitochondrial redox balance.

The upregulation of NDUFA4L2 caught the researchers’ attention as a possible adaptive response. To test this hypothesis, they used small interfering RNA, or siRNA, to knock down NDUFA4L2 expression in glioblastoma cells. The results were striking: NDUFA4L2 knockdown partially restored complex I activity, further increased ROS accumulation, and enhanced the inhibitory effect of stigmasterol on colony formation. This suggests that NDUFA4L2 serves as a compensatory mechanism that glioblastoma cells deploy to maintain redox homeostasis under mitochondrial stress, and that removing this safety net makes the cells more vulnerable to the compound’s effects.

The team validated their key mechanistic findings, including complex I activity, mitochondrial ROS accumulation, and NDUFA4L2 expression, in a second glioblastoma cell line, U251, strengthening the case that these effects are not limited to a single cellular model. All animal experiments were conducted in accordance with the Guidelines for the Care and Use of Laboratory Animals and were approved by the Biomedical Ethics Committee of Xi’an Jiaotong University Health Science Center, ensuring that the preclinical work met rigorous ethical and welfare standards.

The broader significance of this study lies in its framing of mitochondrial metabolic adaptation as a therapeutic vulnerability in glioblastoma. Rather than simply trying to kill tumor cells with cytotoxic agents, the approach described here aims to exploit the tumor’s dependence on mitochondrial function and redox balance. By inducing mitochondrial dysfunction and oxidative stress simultaneously, and by blocking the adaptive response that would normally allow cells to cope with such stress, stigmasterol and compounds like it may represent a new class of metabolic therapeutics for this devastating disease.

Of course, considerable work remains before these findings can be translated into clinical practice. The current study was conducted in cell culture and xenograft models, and the pharmacokinetics, bioavailability, and safety profile of stigmasterol in humans with glioblastoma would need to be established through formal clinical trials. The blood-brain barrier, a formidable obstacle for any therapeutic agent targeting brain tumors, would also need to be addressed. Nevertheless, the identification of NDUFA4L2 as a potential adaptive response to mitochondrial stress offers a concrete molecular target for future drug development, and the demonstration that targeting mitochondrial metabolic adaptation can suppress glioblastoma growth provides a compelling proof of concept for a strategy that may ultimately benefit patients facing one of medicine’s most stubborn cancers.

Subject of Research: Cancer Research

Article Title: Stigmasterol suppresses glioblastoma growth through mitochondrial dysfunction and oxidative stress

Article References: Gao, B., Yun, P., & Liang, C. (2026). Stigmasterol suppresses glioblastoma growth through mitochondrial dysfunction and oxidative stress. BMC Cancer. https://doi.org/10.1186/s12885-026-17184-8

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17184-8

Keywords: glioblastoma, stigmasterol, mitochondrial dysfunction, oxidative stress, NDUFA4L2, cancer metabolism, suppresses, growth, mitochondrial, dysfunction, oxidative, stress