Chemoresistance remains one of the most stubborn problems in lung cancer treatment, and a growing body of work points to cancer stem-like cells as a central driver of that resistance. A new study published in Cellular Oncology reports that a synthetic hydroxylated chalcone derivative, designated UR-2, can selectively attack these stem-like cells by dismantling a mitochondrial redox signaling pathway that they depend on for survival.
The research team used CD133-positive lung cancer organoid and xenograft models to probe how UR-2 exerts its anticancer activity. Quantitative proteomic profiling of the treated organoids identified mitochondrial Thioredoxin-2, the protein product of the TXN2 gene, as a key regulator of the redox signaling changes triggered by the compound.
Functional experiments showed that UR-2 preferentially inhibited the growth, self-renewal and clonogenic capacity of CD133-positive lung cancer organoids, while exerting minimal effects on CD133-negative cells. That selectivity matters, because it suggests the compound may target the subpopulation of cells thought to seed relapse and resist standard therapy, rather than acting as a general cytotoxin.
The mechanistic chain the authors describe runs from the mitochondria outward. UR-2 reduced both TXN2 messenger RNA and TRX2 protein expression. The loss of this mitochondrial antioxidant system allowed intracellular reactive oxygen species to accumulate, which was followed by mitochondrial membrane depolarization, release of cytochrome c, activation of the pro-apoptotic protein Bax, and ultimately Caspase-3-dependent apoptosis.
The study also connected the compound to stemness signaling. UR-2 treatment was associated with decreased β-catenin expression, which the authors interpret as an attenuation of the stemness programs that sustain cancer stem-like cells.
Two rescue experiments support the idea that TRX2 sits upstream of the observed cytotoxicity. When the researchers restored TRX2 signaling with 17β-estradiol, or when they scavenged reactive oxygen species using N-acetyl-L-cysteine, the UR-2-induced ROS accumulation, mitochondrial dysfunction, apoptosis and β-catenin downregulation were all significantly attenuated. In other words, blocking the downstream consequences of TXN2 loss softened the compound’s effects, consistent with disruption of the TXN2/TRX2-mediated mitochondrial redox pathway being a key upstream event in UR-2 cytotoxicity.
Against existing drugs, UR-2 performed favorably in the organoid models. The compound showed greater anti-tumor activity than 5-fluorouracil and cisplatin in CD133-positive organoids, the very cell population in which chemoresistance is most pronounced. In corresponding xenograft models, UR-2 significantly suppressed tumor growth, and the treated tumors showed a reduced abundance of CD133-positive cells along with a shift in the BCL-2/Bax balance toward a pro-apoptotic state.
Collectively, the authors argue that the TXN2/TRX2-ROS axis functions as a critical regulator of cancer stem-like cell survival, and that UR-2 suppresses stemness while promoting mitochondrial apoptosis through disruption of redox homeostasis. They present this as evidence of the compound’s therapeutic potential for targeting chemoresistant lung cancer.
Several caveats are worth keeping in view. The findings come from organoid and xenograft models, which reproduce aspects of tumor biology but do not establish efficacy or safety in patients. The article is being shared early as a peer-reviewed, accepted manuscript that remains subject to further editorial edits before the final version of record. Translating a selective redox-targeting strategy from the laboratory into clinical practice will require the usual sequence of pharmacological development, toxicity assessment and controlled trials, and the current study does not address those steps. Still, the work adds a concrete molecular target to the search for therapies aimed at the stem-like cells that conventional chemotherapy leaves behind.
Subject of Research: A hydroxylated chalcone derivative that disrupts the mitochondrial Thioredoxin-2–ROS axis to induce apoptosis in CD133-positive lung cancer organoids and xenografts.
Article Title: A hydroxylated chalcone derivative disrupts the mitochondrial Thioredoxin-2–ROS axis to induce apoptosis in CD133+ lung cancer organoids
Article References: Baek, S., Choi, S. L., Lee, J. J., Kim, E. J., Lee, J.-H., Yang, J.-Y., Park, J. H., Kim, B. S., Moon, B. S., Lee, S. Y., Seo, J.-B., Kim, H.-J., Lee, S.-H., Yoon, C.-W., & Lee, K. P. (2026). A hydroxylated chalcone derivative disrupts the mitochondrial Thioredoxin-2–ROS axis to induce apoptosis in CD133+ lung cancer organoids. Cellular Oncology. https://doi.org/10.1007/s13402-026-01301-7
Image Credits: AI Generated
DOI: 10.1007/s13402-026-01301-7
Keywords: lung cancer, cancer stem-like cells, chalcone, Thioredoxin-2, reactive oxygen species, apoptosis, organoids, xenograft, CD133, mitochondria, drug resistance, redox signaling
News Source: Nathaniel Bowman. (October 29, 2026). Chalcone compound UR-2 kills stem-like lung cancer cells by disrupting mitochondrial redox signaling. Scienmag.
