In several of the interviews with Dr. Mercola, we touched upon the role of reactive oxygen species (ROS) in health and diseases in the context of the metabolic theory. Most doctors hold the opinion that generating massive amounts of ROS is a normal “price” to pay for high oxidative metabolism, and the higher the metabolic rate the more ROS are generated. This is one of the core arguments in favor of the so-called “rate of living theory”, which says simply that the higher the metabolism, the shorter the lifespan of an organism will be. However, unbeknownst even to most doctors, 98%-99% of ROS are generated not during normal oxidative metabolism (forward electron flow), but during so-called reverse electron flow. The latter happens whenever there is a functional or physical block at one or more of the electron transport chain (ETC) complexes, which leads to build up of electrons and thus reverse flow, which results in ROS being formed when the unpaired electrons react with molecular oxygen. Not only does reverse flow result in a dramatic shift of the redox status towards reduction, but the build-up of ROS leads to direct structural damage to various cell proteins, as well as any intracellular structure containing polyunsaturated lipids. As such, the role of ROS in many chronic conditions has already been recognized and strategies for ROS mitigation have been proposed as prevention/treatment of many diseases. What has not been widely acknowledged is that in the absence of exogenous agents capable of blocking or more of the ETC complexes (e.g rotenone, metformin, etc), reverse electron flow happens quite easily and is in fact responsible for the majority of ROS production simply as a result of shifting the metabolic substrate from glucose to fat (Randle Cycle). Namely, if the Randle Cycle (RC) shifts sufficiently in favor of fat oxidation, that results in depletion of the FAD co-factor, and thus a block at ETC Complex II. In other words, all that is needed for massive generation of ROS is to switch from oxidizing primarily glucose to oxidizing primarily fat. That sounds shocking and counter-intuitive, considering the world (and medicine) has gone crazy over low-carb diets lately, but it is well-known and undisputed biochemical fact. And since the pathological role of ROS is undisputed even by mainstream medicine, one could reasonably says that high-fat / low-carb diets are expected to cause serious health problems even in the absence of exogenous pathological agents (e.g. pharma drugs, endocrine disruptors, stress, etc). It looks like one of those health problems driven by ROS is cancer aggressiveness and metastases. The study below demonstrated that mitochondrial ROS strongly promotes cancer metastases by increasing inflammation, and that dampening said ROS almost completely prevented metastases of a human breast cancer model. In other words, high -fat / low-carb diets may cause something much more serious than obesity, insulin resistance and diabetes, even in the absence of additional pathological factors that are ubiquitous in modern life.
https://www.nature.com/articles/s41420-025-02516-7
“…Although recent research has established that gasdermin D (GSDMD), a factor that drives pyroptosis, is essential for cell death and inflammation, its involvement in cancer metastasis has yet to be elucidated. In this study, GSDMD was significantly increased in lung neutrophils at the metastatic stage from a murine orthotropic 4T1 breast cancer model. Moreover, the N terminal domain from cleaved GSDMD exhibited a positive correlation with increased mitochondrial reactive oxygen species (mROS) and serum high mobility group box 1 (HMGB-1) levels. Mechanistically, mROS inhibition significantly suppressed GSDMD-N oligomerization and pore formation. In addition, the activation of GSDMD significantly enhanced the formation of neutrophil extracellular traps (NETs) following treatment with Cathepsin C. Within a murine orthotopic breast cancer model using 4T1 cell line, the inhibition of GSDMD through the application of LDC7559 significantly attenuated the metastatic spread of breast cancer to the lung. In addition, knockout of GSDMD reduced lung metastasis in E0771 intravenous injection murine model. Furthermore, inhibition of GSDMD reduced the number of myeloid derived suppressor cells (MDSC) in the metastatic lung of breast cancer mouse model, while concurrently increasing both the percentage and total cell count of CD8+ T cells, suggesting that mitochondrial dysfunction-dependent GSDMD activation promotes tumor microenvironment immunosuppression and NETs. GSDMD represents a promising therapeutic target for mitigating the metastatic progression of breast cancer to the lung.”
