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Updated: Aug 7, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Molecular Mechanisms of Nemorosone-Induced Ferroptosis in Cancer Cells
Roberto Fernández-Acosta1, Behrouz Hassannia2,3,4, Jurgen Caroen5
1Department of Pharmacy, Institute of Pharmacy and Food, University of Havana, 222 St. # 2317, La Coronela, La Lisa, Havana 13600, Cuba.
Abstract:
Ferroptosis is an iron-dependent cell death-driven by excessive peroxidation of polyunsaturated fatty acids (PUFAs) of membranes. A growing body of evidence suggests the induction of ferroptosis as a cutting-edge strategy in cancer treatment research. Despite the essential role of mitochondria in cellular metabolism, bioenergetics, and cell death, their function in ferroptosis is still poorly understood. Recently, mitochondria were elucidated as an important component in cysteine-deprivation-induced (CDI) ferroptosis, which provides novel targets in the search for new ferroptosis-inducing compounds (FINs). Here, we identified the natural mitochondrial uncoupler nemorosone as a ferroptosis inducer in cancer cells. Interestingly, nemorosone triggers ferroptosis by a double-edged mechanism. In addition to decreasing the glutathione (GSH) levels by blocking the System xc cystine/glutamate antiporter (SLC7A11), nemorosone increases the intracellular labile Fe2+ pool via heme oxygenase-1 (HMOX1) induction. Interestingly, a structural variant of nemorosone (O-methylated nemorosone), having lost the capacity to uncouple mitochondrial respiration, does not trigger cell death anymore, suggesting that the mitochondrial bioenergetic disruption via mitochondrial uncoupling is necessary for nemorosone-induced ferroptosis. Our results open novel opportunities for cancer cell killing by mitochondrial uncoupling-induced ferroptosis.
Insights
Nemorosone, a natural compound, induces cancer cell death through ferroptosis by disrupting mitochondrial energy production and depleting glutathione. This discovery offers new avenues for cancer treatment research.
Area of Science:
- Biochemistry
- Cell Biology
- Cancer Research
Background:
- Ferroptosis, an iron-dependent cell death, is a promising cancer treatment strategy.
- Mitochondria's role in ferroptosis is increasingly recognized, offering new therapeutic targets.
- Cysteine-deprivation-induced (CDI) ferroptosis highlights mitochondria's importance.
Purpose of the Study:
- To identify novel ferroptosis-inducing compounds (FINs) targeting mitochondria.
- To investigate the mechanism of nemorosone, a natural mitochondrial uncoupler, in inducing ferroptosis.
Main Methods:
- Utilized nemorosone and its structural variant (O-methylated nemorosone) in cancer cell models.
- Assessed ferroptosis induction by measuring glutathione (GSH) levels and labile Fe2+ pool.
- Investigated the role of mitochondrial uncoupling in nemorosone-induced cell death.
Main Results:
- Nemorosone effectively induces ferroptosis in cancer cells.
- Nemorosone decreases GSH by inhibiting SLC7A11 and increases labile Fe2+ via HMOX1 induction.
- Mitochondrial uncoupling is essential for nemorosone-mediated ferroptosis, as a non-uncoupling variant lost its cell death-inducing capacity.
Conclusions:
- Nemorosone is a novel ferroptosis inducer acting through a dual mechanism involving mitochondrial uncoupling and altered cellular redox state.
- Mitochondrial bioenergetic disruption is a critical component of nemorosone-induced ferroptosis.
- This study presents mitochondrial uncoupling-induced ferroptosis as a new strategy for cancer therapy.
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