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Updated: Dec 11, 2025
Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
Published on: March 17, 2023
Mitochondrial uncoupling and the disruption of the metabolic network in hepatocellular carcinoma
Lilia Turcios1, Francesc Marti1, David S Watt2,3
1Department of Surgery, Transplant Division, College of Medicine, University of Kentucky, Lexington, KY, USA.
Background:
Hepatocellular Carcinoma (HCC) is the third most common cause of cancer related death worldwide. Adequate treatment options for patients with advanced HCC are currently limited.
Materials And Methods:
We studied the anti-HCC effect of FH535 and a novel derivative Y3, on proliferation, mitochondrial function and cellular metabolism focusing on the three key substrates, glutamine, glucose, and fatty acids.
Results:
FH535 and Y3 disrupted mitochondrial redox control in HCC cells that resulted from uncoupling mechanisms that increased proton leakage and decreased ATP production leading to apoptosis. The uncoupling effects of the sulfonamides in HCC cells were supported by the loss of activity of the methylated analogs. The accumulation of ROS significantly contributed to cell damage after the impaired autophagic machinery. These sulfonamides, FH535 and Y3, targeted glutamine and fatty acid metabolism and caused HCC cell reprograming towards the preferential use of glucose and the glycolytic pathway.
Conclusions:
FH535, and Y3, demonstrated potent anti-HCC activity by targeting OXPHOS, increasing dangerous levels of ROS and reducing ATP production. These sulfonamides target glutamine and FA metabolic pathways significantly increasing the cellular dependency on glycolysis.
Insights
FH535 and Y3 show potent anti-Hepatocellular Carcinoma (HCC) activity by disrupting mitochondrial function and altering cellular metabolism. These compounds induce apoptosis and increase reliance on glycolysis, offering new therapeutic avenues for advanced HCC.
Area of Science:
- Oncology
- Biochemistry
- Cell Biology
Background:
- Hepatocellular Carcinoma (HCC) is a leading cause of cancer mortality globally.
- Limited effective treatments exist for advanced HCC patients.
Purpose of the Study:
- To investigate the anti-HCC effects of FH535 and its derivative Y3.
- To examine their impact on proliferation, mitochondrial function, and cellular metabolism (glutamine, glucose, fatty acids).
Main Methods:
- Studied the effects of FH535 and Y3 on HCC cell lines.
- Assessed proliferation, mitochondrial function, ATP production, ROS levels, and metabolic substrate utilization.
- Utilized methylated analogs to confirm uncoupling mechanisms.
Main Results:
- FH535 and Y3 disrupted mitochondrial redox control, uncoupling oxidative phosphorylation (OXPHOS) and reducing ATP production.
- Increased reactive oxygen species (ROS) accumulation contributed to cell damage.
- Targeted glutamine and fatty acid metabolism, reprogramming cells to favor glycolysis.
Conclusions:
- FH535 and Y3 exhibit potent anti-HCC activity.
- Mechanism involves targeting OXPHOS, increasing ROS, and reducing ATP.
- These sulfonamides shift HCC cell metabolism towards glycolysis.
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