bims-mignad 2025-07-13 papers

Issue of 2025–07–13
three papers selected by
Melisa Emel Ermert, Amsterdam UMC

Crit Rev Oncol Hematol. 2025 Jul 08. pii: S1040-8428(25)00232-X. [Epub ahead of print] 104844

Novel Insight into The Warburg effect: Sweet Temptation.

Heng Zhang, Sinian Liu, Shengfeng Fu, Qihan Zhao, Yuheng Wang, Yin Yuan, Changhe Zhang.

Metabolic reprogramming is an important feature of tumors, and reprogramming of glucose metabolism was the earliest identified marker of metabolic alterations in tumors. The Warburg effect describes the propensity of tumor cells to preferentially metabolize glucose through glycolysis, even in the presence of oxygen, rather than relying on oxidative phosphorylation. This unique metabolic phenotype empowers cancer cells to proliferate and invade indefinitely, inducing metabolic adaptations that provide cancer cells with a survival advantage in hypoxic and nutrient-poor environments. Various mechanisms are able to promote the Warburg effect, and the adverse effects are complex and diverse. This review primarily examines the Warburg effect in tumor cells, and systematically investigates the influence of factors such as glycolytic enzymes, mitochondrial function, tumor microenvironment, and oncogenes on the Warburg effect. It comprehensively summarizes the underlying mechanisms of reactions and corresponding targeted drugs while discussing their potential applications in anticancer therapy. Elevated aerobic glycolysis activity represents a key characteristic of tumor cells, which can offer new insights for early diagnosis and treatment of cancer. Furthermore, in the context of recent research advancements, this review discusses how these insights may contribute to the development of novel therapeutic strategies. which is a difficult and meaningful challenge.

Keywords: Metabolism reprogramming; Oncogenes; Post translational modifications; Tumor Microenvironment; Tumor glycolysis; the Warburg effect

DOI: https://doi.org/10.1016/j.critrevonc.2025.104844

Free Radic Biol Med. 2025 Jul 08. pii: S0891-5849(25)00818-4. [Epub ahead of print]

Modulation of NAD metabolism by oxygen availability.

Johannes Burtscher, Tobias Dünnwald, Giuseppe Paglia.

Reduced oxygen availability (hypoxia) can result in decreased energy levels, perturbed redox homeostasis and permanent cellular damage. Efficient hypoxic stress responses and the induction of protective adaptations are crucial to prevent hypoxic damage and can be targeted to improve cellular resilience and health. Nicotinamide adenine dinucleotide (NAD) metabolism is highly sensitive to changes in oxygen availability and interacts with other stress pathways, such as the oxygen-regulated transcription factors hypoxia-inducible factors (HIFs), to orchestrate cellular responses and adaptations to hypoxia. We evaluate what is known about this interaction, how it may be modulated and which benefits could be expected from related therapeutic interventions. We further discuss, which future research is needed to develop therapeutic strategies targeting the hypoxic response-NAD axis.

Keywords: hypoxia inducible factor; metabolic reprogramming; mitochondrial functions; nicotinamide adenine dinucleotide; oxidative stress; oxygen; redox homeostasis

DOI: https://doi.org/10.1016/j.freeradbiomed.2025.07.014

bioRxiv. 2025 Jul 05. pii: 2025.07.01.662602. [Epub ahead of print]

Labile iron pool dynamics do not drive ferroptosis potentiation in colorectal cancer cells.

Varun Ponnusamy, Deahzana R Randall, Zheng Hong Lee, Nupur K Das, Liang Zhao, Kathryn Buscher, Sumeet Solanki, Adam R Renslo, Peggy P Hsu, Yatrik M Shah.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. CRC tumors exhibit aberrant iron accumulation, which supports tumor cell proliferation through multiple metabolic pathways. However, the oncogenic benefits of elevated iron must be counterbalanced by its potential to catalyze oxidative damage via reactive oxygen species generated from labile, redox-active iron. Ferroptosis is a regulated, non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation. This process is tightly controlled by the selenoenzyme glutathione peroxidase 4 (GPX4), which reduces lipid peroxides and can be pharmacologically inhibited by agents such as RSL3 and JKE1674. A key source of redox-active iron is the labile iron pool (LIP), yet its role in regulating ferroptosis remains incompletely defined. To examine this, we supplemented CRC cells with exogenous iron following pharmacologic induction of ferroptosis. Iron supplementation significantly reduced cell viability, suggesting that expansion of the LIP potentiates ferroptotic cell death. However, whether ferroptosis is accompanied by dynamic changes in the LIP, and if such changes are mechanistically required for its potentiation, was unknown. To further characterize this response, we profiled the expression of iron regulatory genes under ferroptotic conditions and observed no change in transcriptional response in iron homeostasis genes. When using a fluorescent probe for labile iron, we found that the LIP did not measurably increase during ferroptosis induction. These findings suggest that the LIP itself does not expand after the initiation of ferroptosis to become the primary driver of ferroptotic potentiation.

DOI: https://doi.org/10.1101/2025.07.01.662602