What if I told you that the rusting of an old pipe could actually save your body from cancer?

What if I told you that the rusting of an old pipe could actually save your body from cancer? I know what you are thinking, but before we talk about this, let’s start from the basics.

We already know that cells in our body constantly undergo a cycle of dividing and dying in the process. Cell death plays an important role by removing damaged cells, sculpting organs during development, and maintaining balance. For decades, scientists thought that cells either die by apoptosis or necrosis. However, in 2012, they discovered the rusted cousin of apoptosis — ferroptosis — which altered the understanding of diseases from cancer to neurodegeneration.

THE DEATH WE THOUGHT WE UNDERSTOOD

APOPTOSIS: Programmed cell death

Apoptosis is the major form of regulated cell death characterized by caspase activation, cell shrinkage, chromatin condensation, and membrane blebbing. Apoptosis plays central roles in development, immune tolerance, tissue remodeling, and tumor suppression. Basically, no mess, no inflammation, and no collateral damage. What cancerous cells do is they completely evade this cell death, which leads to uncontrolled cell growth causing tumors.

NECROSIS: Accidental cell death

While apoptosis is regulated, necrosis is messy. Necrosis occurs when cells die due to trauma, toxins, physical injury, or lack of oxygen. The cell swells, membranes rupture, intracellular contents spill out, and inflammation follows almost immediately. So to say, it is an accidental death rather than cellular suicide.

However, surprisingly, necrosis can also be regulated, which is known as necroptosis. It is characterized by organelle swelling, plasma membrane rupture, and release of intracellular components such as DAMPs (damage-associated molecular patterns). We will talk about it sometime else in detail.

Autophagy: Death by Self-Digestion

Autophagy (literally “self-eating”) is where cells break down and recycle their own components. Usually, this is a survival mechanism, helping cells through tough times by cannibalizing their own parts for energy. But excessive autophagy can lead to cell death, though whether this constitutes a distinct form of death or just an extreme stress response remains debated.

Now, remember I talked about rusting of an old pipe in the beginning. Well, in this case pipe would be cells. So what exactly is this cellular rust?

STORY TIME

In the early 2010s, researchers led by Brent Stockwell were testing compounds on cancer cells, trying to gain an understanding of drugs that killed RAS-mutant cancer cells. Incidentally, they stumbled on erastin. Erastin caused cell death in cancerous cells without showcasing any hallmark characteristics of either apoptosis or necrosis. There was no DNA fragmentation, no characteristic shrinkage, and none of the usual markers. The mitochondria — the cell’s power plants — looked strange, shrunken with denser membranes. But what really stood out was the state of the cell membrane itself.

After extensive investigation, they realized they were witnessing an entirely new form of cell death, one driven by a process that sounded more like industrial chemistry than biology: iron-catalyzed lipid peroxidation.

This was officially named ferroptosis in 2012. “Ferro” for iron, “ptosis” for falling or death.

ATTACK

We know that when iron rusts, it catalyzes oxidation reactions which lead to metal breakdown. Similarly, in ferroptosis, iron accumulates within the cell. Iron is essential for life, but as with everything else, excess of it causes damage. Free iron can react with oxygen and generate highly reactive oxygen species. These ROS then interact with membrane lipids, especially polyunsaturated fatty acids, and break down their double bonds.

These attacks convert PUFAs into lipid peroxides by adding oxygen to fats. This is known as lipid peroxidation. These lipid peroxides then damage neighbouring molecules, causing a chain reaction. As lipid peroxides accumulate, the cell membrane becomes weaker, thinner, and leaky. At this point, the cell is under severe stress and is pushed toward ferroptotic death.

DEFENSE

I am sure you’re wondering, can the body not fight these? The answer is yes — to protect itself, the cell relies on glutathione peroxidase 4, or GPX4, a powerful defense enzyme. The role of GPX4 is to detect lipid peroxides and convert them into harmless lipid alcohols to prevent damage. GPX4 relies on a small antioxidant molecule made from amino acids known as glutathione for its protection.

As long as GPX4 is active and glutathione levels are sufficient, the cell can neutralize the attack and survive. However, when glutathione is depleted or GPX4 is inhibited, this defense collapses. Without GPX4, lipid peroxides accumulate uncontrollably, membranes lose their integrity, and ferroptosis becomes unavoidable.

ADVANCEMENTS

This has led researchers to consider ferroptosis induction as a promising treatment option for cancer, especially for tumors that have become resistant to traditional treatments like apoptosis-inducing chemotherapy. Until now, researchers have identified many compounds that can cause ferroptosis in cancer cells.

Some of them are erastin and sulfasalazine, which function by blocking cystine uptake, which depletes glutathione and indirectly disables GPX4. In addition, RSL3 directly inhibits GPX4 and induces ferroptotic death and has demonstrated strong anticancer effects in several models like mesenchymal-type tumors, while FIN56 focuses on depleting coenzyme Q10 (CoQ10), which weakens lipid antioxidant defenses and encourages ferroptosis.

BEYOND CANCER

Now, as every coin has two sides, ferroptosis can also have negative effects in the body. Ferroptotic deaths are one of the major reasons behind many neurological conditions like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and stroke damage. This is because the brain is rich in iron and polyunsaturated fatty acids — both playing an important role in ferroptosis. And when neurons die ferroptotically, we lose them permanently. To protect the brain from ferroptosis, we generally use anti-ferroptotic drugs, also known as ferrostatins.

BACK TO THE FUTURE

All in all, scientists are actively exploring the implications of ferroptosis, whether positive or negative, and are identifying new regulators that either induce or prevent ferroptosis depending on clinical need.

Within the next decade, we can expect to see ferroptosis-targeting therapies in clinical use. The cancer drug that works by making cells rust to death, along with other combination therapies. The neuroprotective medication that prevents iron-driven neuronal loss. The kidney-protective agent that blocks lipid peroxidation.

This perfectly showcases how little things — which in our case was a minute cell — could cause profound effects. The next time you see rust forming on metal, remember: that same chemistry might one day cure cancer or save neurons from degenerative diseases. Science often hides its biggest breakthroughs in the smallest, most unexpected places.