In many of the podcasts I have done over the years, as well as many of my posts, I have highlighted the role of the GSH (the reduced form of glutathione) not only as a master antioxidant, but also as a redox indicator when used in conjunction with its oxidized version known as glutathione disulfide (GSSG). Namely, the GSH/GSSG ratio is a very useful biomarker of mitochondrial redox status, together with (mitochondrial) NAD+/NADH, acetoacetate/hydroxybutyrate and pyruvate/lactate ratios. Medicine does not seem to think much of GSSG except as a biomarker of “oxidative” stress, and it is almost universally viewed as a biomarker of poor health. There are a multitude of studies focusing on GSH levels and trying to demonstrate that elevating GSH levels is beneficial. Now, in conditions of true oxidative stress, GSH may indeed be helpful. However, as discussed on several recent interviews, what most doctors consider “oxidative” stress is actually “reductive” stress, and as a reductant GSH can make thing much worse in such conditions. It is well known that the mitochondrial redox status of patients with virtually any chronic disease is heavily shifted towards reduction. This seems to be true especially in cancer, and it has already been shown convincingly that intracellular GSH levels (and especially the GSH/GSSG ratio) are elevated in virtually all cancer types. It has been proposed that “cancer” cells simply accumulate this antioxidant to protect themselves from reactive oxygen species (ROS) and that GSH does not really play a role in the cancerization and metastatic process itself. However, this view has been challenged by multiple other studies showing that lowering GSH, increasing GSSG, or both can have dramatic effects on even advanced cancers, often leading to cancer remission or even complete tumor regression. Oxidizing agents such as the quinone molecules, we all as pro-metabolic substances such as aspirin, thyroid, dinitrophenol (DNP), etc are all known to powerfully lower the GSH/GSSG ratio and (non)coincidentally they have all shown promise as possible treatments for cancer.
The study below demonstrates that GSH is actually a primary driver of cancer metastasis, due to its role as an activator of signalling pathways associated with hypoxia. Virtually all such pathways are “anabolic” and are used by cancer cells not only to enhance their survival, but also to synthesize various metabolites necessary for cell growth and division (a hallmark of all cancers). Since GSH is transported inside the mitochondria via an active transport mechanism known as SLC25A39, the study examined the role of that transporter in cancer growth and metastasis and found that blocking the transporter (and thus lowering GSH levels and GSH/GSSG ratio) was therapeutic and stopped the metastasis process. However, blocking of that transport mechanism could potentially lead to lowering of the total glutathione pool (GSH+GSSG) inside the mitochondria, which may have negative effects on metabolically normal cells of people diagnosed with cancer. As such, I still believe that a preferable approach is not to block GSH transport, but to increase its conversion into the oxidized version GSSG, which does not activate the hypoxic pathways and can also be converted into GSH by normal cells if needed. In addition, lowering the GSH/GSSG ratio by increasing GSH oxidation has metabolic benefits of its own such as the lowering of lactate (which is a known cancer promoted and the study below again confirmed lactate’s oncogenic role). In other words, quinones, aspirin, thyroid, niacinamide and other pro-metabolic substances are probably a safer approach to treating cancer than messing with the active transport mechanisms of one of the most important molecules in the human organism, whose physiological role (aside from being an antioxidant) is still largely unknown.
https://doi.org/10.1158/2159-8290.CD-24-1556
https://www.newswise.com/articles/mitochondrial-antioxidant-found-to-drive-breast-cancer-metastasis
“…Among thousands of mitochondrial compounds, one stood out: glutathione. A major antioxidant involved in reducing oxidative stress, enhancing metabolic detoxification, and regulating the immune system, glutathione levels were found to have skyrocketed in metastatic cancer cells that invaded the lung. To further confirm the findings, the team used a spatial metabolomics technique that allowed them to visualize the distribution of glutathione directly within lung tissues. They then shifted their focus toward mitochondrial membrane proteins, screening for transporters that stood out as essential for metastatic cells growing in the lung. Once again, a clear frontrunner emerged: SLC25A39, the mitochondrial glutathione transporter. The findings closed the loop, linking a metabolite and its transporter to metastasis by demonstrating that mitochondrial glutathione import via the SLC25A39 transporter is essential for cancer spread. Birsoy and colleagues also found how mitochondrial glutathione drives cancer spread: not by acting as an antioxidant—an effect ruled out through multiple experiments—but by signaling to activate ATF4, a transcription factor that helps cancer cells survive in low-oxygen conditions. This also pinpointed when glutathione is specifically required: during the early steps of metastatic colonization, when cancer cells adapt rapidly to the stressful environment of a new tissue. This work builds on recent significant work from the Birsoy lab. In 2021, his team was the first to demonstrate that SLC25A39 is the transporter that brings glutathione into the mitochondria; in 2023, they showed that SLC25A39 is not only a transporter but a dynamic sensor that regulates the amount of glutathione in the mitochondria and adjusts those levels accordingly. So when this metabolite and its mitochondrial transporter showed up in cancer screenings, Birsoy knew where to take his experiments next. “Because we found this transporter earlier and knew how to block the entry of glutathione, we already had the tools necessary to investigate its role in cancer metastasis,” he says. The findings may have clinical implications—especially since the team also found that breast cancer samples from patients whose disease had spread to the lung showed elevated SLC25A39, and that higher SLC25A39 expression was strongly correlated with poorer overall survival in breast cancer patients. One day, a small molecule that targets this metabolite by blocking its transporter could potentially forestall breast cancer metastasis, with fewer side-effects than sweeping therapies that target more general cellular processes.”
