A 2026 cancer discovery has drawn attention to a signalling pathway that food, breath, sunlight, and stomach acid have been governing all along. Most people are blocking it without knowing.
In 2026, researchers at the Weizmann Institute of Science published a finding in the journal Cancer Research that reframed a well-known drug. Professor Ayelet Erez and Dr. Yarden Ariav demonstrated that sildenafil, the compound sold as Viagra, interferes with the ability of cancer cells to access the cholesterol they require in order to spread.
The mechanism is specific. Sildenafil blocks an enzyme called phosphodiesterase type 5, known as PDE5. Blocking PDE5 allows a signalling molecule called cyclic GMP, or cGMP, to accumulate inside cells. When cGMP rises, it interferes with a transport protein called NPC1, which is responsible for moving cholesterol out of internal storage compartments and into the cell membrane. Cholesterol becomes trapped. And a cancer cell that cannot reorganise its membrane cannot detach, migrate, and establish itself elsewhere.
In mouse models and human cancer cell cultures, sildenafil reduced metastatic spread to the lungs across breast, lung, and colon cancer models. In twenty years of medical records covering five million patients in Israel’s Clalit health database, men who had filled at least three sildenafil prescriptions before a cancer diagnosis showed a 26% lower risk of death within five years. Among those also taking statins, the figure reached 32%.
Professor Erez’s own summary of the work is the sentence worth sitting with: their study underscores the importance of treating the whole patient rather than only the cancer when tailoring the most effective therapy.
This article is not about sildenafil. It is about the pathway sildenafil happened to illuminate, and about what has been happening to that pathway in ordinary bodies, through ordinary daily choices, for decades before anyone thought to look at it this way.
The Pathway Runs Whether or Not You Take a Drug
The nitric oxide to cGMP pathway is not a pharmaceutical invention. It is one of the most fundamental signalling systems in human physiology, and it runs continuously in every blood vessel in the body.
Here is how it works when it works.
The endothelium, the single-cell-thick lining of every blood vessel, contains an enzyme called endothelial nitric oxide synthase, or eNOS. This enzyme converts the amino acid L-arginine into nitric oxide, abbreviated NO. Nitric oxide diffuses into the smooth muscle of the vessel wall, where it activates an enzyme called soluble guanylyl cyclase. That enzyme produces cGMP. cGMP relaxes the smooth muscle, the vessel widens, and blood flows more freely.
PDE5 is the off switch. It degrades cGMP, allowing the vessel to return to baseline tone. The system is designed to pulse, not to stay permanently open.
What the Weizmann research adds is that cGMP does more than regulate vessel diameter. It participates in the regulation of intracellular cholesterol trafficking through its effect on the NPC1 transporter. Which means the same signalling molecule that determines how your blood vessels behave also participates in determining how cholesterol moves inside your cells.
This is where the terrain question begins. Because in most people presenting with chronic illness, this pathway is not running at capacity. It has been progressively compromised, often at several points simultaneously, by inputs so ordinary that nobody has thought to name them as a cluster.
The First Blockade: Acid Suppression
This is the connection that deserves the most attention, because it is the least discussed and the most common.
Dietary nitrate is the primary raw material for a second, entirely separate nitric oxide production pathway that runs alongside the eNOS route. Nitrates from green leafy vegetables and beetroot are absorbed in the small intestine, enter the bloodstream, and are then concentrated in the salivary glands. Specific bacteria on the surface of the tongue reduce these nitrates to nitrites. The nitrite-rich saliva is swallowed.
And then the critical step: in the acidic environment of the stomach, nitrite is protonated into nitrous acid, which decomposes to release nitric oxide directly.
That reaction requires acid. Specifically, it requires the gastric pH of roughly 1.5 to 3.5 that a healthy stomach maintains.
Proton pump inhibitors, the class of drugs including omeprazole, esomeprazole, lansoprazole, and pantoprazole, suppress gastric acid production by eighty to ninety-five percent. They typically raise gastric pH into the range of 4 to 6. At that pH, the nitrite-to-nitric-oxide conversion largely does not occur.
A person taking a daily proton pump inhibitor and eating a large salad of rocket, spinach, and beetroot is consuming the correct raw material and losing most of the conversion. The nitrate arrives. The bacteria do their work. And then the reaction that was supposed to produce nitric oxide fails at the final step because the acid required to drive it has been pharmacologically removed.
There is a second, independent mechanism. Research published in Circulation in 2013 by Ghebremariam and colleagues demonstrated that proton pump inhibitors inhibit an enzyme called dimethylarginine dimethylaminohydrolase, or DDAH. DDAH is responsible for breaking down asymmetric dimethylarginine, known as ADMA. ADMA is the body’s own endogenous inhibitor of eNOS. When DDAH is suppressed, ADMA accumulates. When ADMA accumulates, eNOS is inhibited. Nitric oxide production falls.
So proton pump inhibitors compromise nitric oxide production through two entirely separate mechanisms at once. They block the gastric conversion pathway by removing the acid, and they block the enzymatic pathway by allowing the eNOS inhibitor to accumulate.
These are drugs that tens of millions of people take daily, often for years, frequently without a clear end point, and in many cases for symptoms that originate in bile reflux or delayed gastric emptying rather than in acid excess at all.
The Second Blockade: Industrial Seed Oils
Sunflower, corn, soybean, cottonseed, and safflower oils are predominantly composed of linoleic acid, an omega-6 polyunsaturated fatty acid. Linoleic acid is not inherently harmful in the quantities found in whole foods. The issue is concentration, oxidation, and the sheer volume in which these oils now appear in the food supply.
Polyunsaturated fats are chemically unstable. Their double bonds oxidise readily under heat, light, and oxygen exposure. Oxidation produces a family of compounds known as oxidised linoleic acid metabolites, which generate oxidative stress in the tissues where they accumulate. The vascular endothelium, in direct and continuous contact with the bloodstream, is among the most exposed.
Here is the mechanism that matters for this pathway.
eNOS requires a cofactor called tetrahydrobiopterin, abbreviated BH4, in order to function correctly. BH4 is itself highly susceptible to oxidation. When oxidative stress in the endothelium is high, BH4 is oxidised and depleted. And when BH4 is insufficient, eNOS does something clinically significant: it does not simply stop working. It uncouples.
An uncoupled eNOS enzyme continues to consume oxygen but produces superoxide, a damaging free radical, instead of nitric oxide. The enzyme designed to protect the blood vessel begins damaging it. Superoxide also reacts with any remaining nitric oxide to form peroxynitrite, a highly reactive compound that further oxidises BH4, deepening the cycle.
A diet high in industrial seed oils does not simply fail to support nitric oxide production. It converts the primary nitric oxide-producing enzyme into a source of oxidative damage.
The Third Blockade: The Oral Microbiome
The nitrate-to-nitrite conversion described earlier is performed entirely by bacteria. Human cells cannot do it. The species responsible, including members of the Veillonella, Actinomyces, and Rothia genera, live in the biofilm on the posterior surface of the tongue.
Antibacterial mouthwash kills them.
Research published in Free Radical Biology and Medicine by Kapil and colleagues demonstrated that chlorhexidine mouthwash use measurably reduced oral nitrate reduction, lowered circulating nitrite levels, and produced a measurable increase in blood pressure in the study subjects. The effect appeared within days.
Twice-daily antibacterial mouthwash, used for the reasons dentists recommend it, removes a bacterial population that the nitric oxide pathway depends on. The person doing this is following sound dental advice and unknowingly disabling a step in their own vascular signalling.
Broad-spectrum antibiotics have the same effect over a longer horizon, and the oral biofilm can take weeks to recover after a course.
The Fourth Blockade: How You Breathe
The paranasal sinuses produce nitric oxide continuously. Concentrations in the nasal airway are roughly ten to a hundred times higher than in the lower airways or ambient air.
When you breathe through your nose, this nitric oxide is carried into the lungs with each inhalation, where it dilates the pulmonary vasculature, improves the matching of blood flow to ventilated alveoli, and enters systemic circulation. Researchers describe the process as autoinhalation: the body producing its own inhaled vasodilator with every breath.
Mouth breathing bypasses this entirely.
Chronic mouth breathing is common and under-recognised. It occurs with nasal congestion, allergic rhinitis, deviated septum, enlarged adenoids, sleep apnoea, and simple habit. A person who breathes through their mouth during sleep is losing this nitric oxide contribution for seven or eight hours every night, during precisely the window when vascular repair and endothelial maintenance are meant to be at their most active.
The nose is not merely a filter. It is a nitric oxide delivery system, and using it is not optional if the pathway is to run as designed.
The Fifth Blockade: Stillness
The single most potent physiological stimulus for eNOS expression is shear stress: the frictional force of blood moving along the endothelial surface.
Endothelial cells are mechanosensitive. They detect the drag of flowing blood through specialised structures on their surface and respond by upregulating eNOS transcription. More flow means more signal means more enzyme means more nitric oxide capacity.
The inverse holds equally. Prolonged low-flow states, which is what sitting produces in the lower limbs and much of the peripheral circulation, downregulate eNOS expression. The enzyme is produced in smaller quantities because the mechanical signal calling for it has gone quiet.
This is why exercise improves vascular function through a mechanism entirely independent of weight loss, and why the effect begins to reverse within days of stopping. It is not about calories. It is about whether the endothelium is receiving the mechanical signal that tells it to build the machinery.
The Sixth Blockade: Timing
eNOS expression follows a circadian rhythm, with peak activity in the early morning hours. This is coordinated with the broader circadian programme: the liver’s overnight repair cycle, the nocturnal dip in blood pressure that healthy vasculature produces, and the cortisol curve that should be lowest around midnight and rising toward waking.
Late eating, irregular sleep, blue light exposure after dark, and shift work all disrupt this coordination. Chronic sleep deprivation raises ADMA, the eNOS inhibitor discussed earlier. It elevates cortisol at the wrong hours. And it removes the deep sleep during which the vascular endothelium performs its repair.
People who lose the nocturnal blood pressure dip, a pattern clinicians call non-dipping, have measurably worse cardiovascular outcomes. Non-dipping is, in part, an expression of a nitric oxide system that has lost its rhythm.
The Cholesterol Terrain: A Synthesis
The Weizmann research connects cGMP to cholesterol trafficking inside cells. But cholesterol handling in the body is a whole-system process, and each of the four terrain pillars governs a distinct part of it. This is where the picture becomes genuinely useful for anyone thinking about their own health rather than about cancer specifically.
The liver is the only exit. Cholesterol cannot be broken down for energy by human cells. It leaves the body through exactly one route: conversion into bile acids in the liver, secretion into bile, delivery into the small intestine, and excretion in stool. A congested liver with sluggish bile production reduces the capacity of this single exit. Cholesterol that cannot leave remains in circulation and in tissue.
The gut determines how much comes back. Bile acids are largely reabsorbed in the terminal ileum and returned to the liver, a process called enterohepatic recirculation. When bowel transit is slow, more is reabsorbed and less is excreted. Separately, specific gut bacteria convert cholesterol into coprostanol, a compound the intestine cannot absorb. Research published in 2024 identified Oscillibacter species as significant cholesterol-metabolising organisms in the human gut, with abundance correlating inversely with blood cholesterol levels. A depleted microbiome performs less of this conversion, and more cholesterol returns to circulation.
The lymphatic system clears cholesterol from tissue. This connection is the least discussed and among the most important. Reverse cholesterol transport, the process by which HDL particles collect excess cholesterol from peripheral tissues and macrophages and return it to the liver, does not travel primarily through blood vessels from the tissue side. Research published in the Journal of Clinical Investigation by Martel and colleagues demonstrated that the lymphatic vasculature is required for macrophage reverse cholesterol transport. Disrupt lymphatic drainage, and cholesterol clearance from peripheral tissue is impaired even when blood lipid handling appears intact.
Lymphatic stagnation, the fluid retention, tissue puffiness, and sluggish drainage that presents as swollen ankles, morning facial puffiness, and a heavy, congested feeling in the limbs, is not a cosmetic complaint. It is a functional impairment of a cholesterol clearance system.
The nervous system governs the whole rhythm. Vagal tone regulates gut motility, which determines bile acid excretion. Cortisol regulates hepatic lipid handling. Sympathetic dominance suppresses digestion and reduces nitric oxide production. And the circadian rhythm that all of this depends on is a nervous system function before it is anything else.
Four pillars. One integrated cholesterol handling system. The Weizmann finding identifies a cellular-level cholesterol trafficking mechanism that is regulated by a signalling molecule the whole terrain influences.
What the Cases Have Been Showing All Along
Looking back across the case histories in this practice with this pathway in mind produces an uncomfortable clarity. The pattern was present in every one of them, and nobody was calling it by this name.
A woman in her forties presented after prolonged ketogenic dieting with H. pylori infection, bile reflux gastritis, pancreatic inflammation, and elevated inflammatory markers. Her diet during the years preceding her collapse contained no vegetables and no fruit at all, which means it contained essentially no dietary nitrate. She had been placed on proton pump inhibitors, which suppressed the gastric acid required for the nitrite conversion and simultaneously elevated ADMA. She was sedentary by explicit instruction from the dietary community she had joined. Three separate blockades in the same body at the same time, none of them named, all of them contributing to a vascular and metabolic terrain that could not clear what it was carrying.
A woman in her early fifties presented with blood pressure that had been managed with an angiotensin receptor blocker for ten years without anyone asking why it required managing. Hypertension is, at its most fundamental level, a nitric oxide deficiency state. Her daily black tea provided caffeine that constricted vessels on a schedule. Her chronic constipation slowed bile acid excretion. Her sleep was six hours and unrefreshing. When those inputs changed, her readings shifted from 140 over 95 to 114 over 84 in two weeks. The medication had been blocking a receptor downstream while the nitric oxide production upstream had been compromised for a decade.
A woman in her forties presented with fifteen years of rheumatoid arthritis and joints that were beginning to fail. Her chapati was cooked in corn oil, consumed regularly across years. Corn oil is among the highest linoleic acid seed oils in common use. The eNOS uncoupling mechanism described earlier does not only affect blood vessels; it generates superoxide in every tissue where the endothelium is under oxidative pressure, including the small vessels supplying synovial joint tissue. Her joint inflammation and her vascular oxidative burden shared an input.
A woman in her mid-forties presented with two decades of eye strain, light sensitivity, and progressive myopia that three opticians had described as genetic and unchangeable. The retina has the highest oxygen consumption per gram of any tissue in the body and is supplied by some of the smallest calibre vessels in the circulation. Retinal and choroidal perfusion are profoundly nitric oxide dependent. Her cortisol cycled monthly and suppressed thyroid conversion. Her lunch was routinely skipped. When rhythm and nutrient density were corrected, her eyes stopped hurting for the first time in twenty years.
A man in his thirties presented after seventeen years of continuous proton pump inhibitor use with burning feet, brain fog, and fatigue severe enough to limit walking. The B12 depletion explanation is correct and well documented. But burning peripheral neuropathy also has a microvascular component, and seventeen years of suppressed nitric oxide production through both the gastric and the DDAH mechanisms would compromise perfusion in exactly the smallest and most distal vessels first. The feet are where a nitric oxide deficit announces itself earliest.
Five people. Five different presenting complaints. One pathway compromised in every case, through overlapping combinations of the same six ordinary blockades.
An Honest Limit
This article would be less useful if it overstated its case, so here is the necessary caution.
Nitric oxide biology in cancer is genuinely complex and not uniformly beneficial. Nitric oxide exhibits concentration-dependent and context-dependent effects in tumour biology. At certain concentrations and in certain tumour microenvironments, nitric oxide can promote angiogenesis and support tumour growth. At others it is cytotoxic to tumour cells. The relationship is not linear and it is not resolved.
The Weizmann finding is specifically about cGMP elevation affecting NPC1-mediated cholesterol transport. It is not a finding that more nitric oxide is universally protective against cancer. Anyone who tells you otherwise is simplifying past the point of accuracy.
What the terrain argument actually claims is narrower and more defensible: a body in which nitric oxide signalling is chronically suppressed through acid suppression, oxidised seed oils, disrupted oral microbiome, mouth breathing, physical stillness, and circadian disorder is a body with impaired vascular function, impaired tissue perfusion, impaired cholesterol clearance, and elevated systemic oxidative stress. Those are not hypothetical states. They are measurable, and they are the substrate on which chronic disease of many kinds develops.
The research is still early. Professor Erez has stated that the next step is a clinical trial administering sildenafil to women with triple-negative breast cancer. That trial has not reported. Nobody should self-medicate on the basis of this finding, and nobody should stop, start, or alter any prescribed medication without their doctor.
What Restoration Actually Requires
The body does not need a pharmaceutical to run this pathway. It needs the conditions under which the pathway was designed to run.
It needs dietary nitrate from green leafy vegetables and beetroot, arriving in a stomach with sufficient acid to complete the conversion.
It needs an oral microbiome intact enough to perform the bacterial reduction step.
It needs the amino acid precursors for eNOS, and the folate and B vitamins that support BH4 regeneration.
It needs to be free of the concentrated oxidised polyunsaturated fats that deplete BH4 and uncouple the enzyme.
It needs the mechanical signal of movement to maintain eNOS expression.
It needs the nose to be used for breathing, including during sleep.
It needs morning light, which releases nitric oxide from photolabile cutaneous stores through documented photobiomodulation.
It needs the overnight window in which the liver completes digestion early enough to shift to repair, bile production, and the vascular maintenance that the circadian rhythm schedules for those hours.
None of these are exotic. All of them are ordinary. Which is precisely why they have been so easy to lose.
What to Bring to Your Doctor
These questions open a conversation rather than a confrontation, and they are reasonable to ask.
If I have been on a proton pump inhibitor for more than a few months, what is the plan for reassessing whether I still need it, and what is the safest way to reduce it if I do not?
Has anyone assessed whether my reflux symptoms are driven by acid excess, bile reflux, or delayed gastric emptying, since these require different approaches?
Would it be reasonable to check my homocysteine, B12, and folate levels given my medication history?
Do I have a nocturnal blood pressure dip, and would a 24-hour ambulatory monitor be informative in my case?
Is there any indication that I am breathing through my mouth during sleep, and would a sleep assessment be appropriate?
The Terrain Observation
A discovery about a cancer drug has drawn attention to a signalling pathway that has been running in every human body for as long as there have been human bodies. The pathway is governed by what you eat, whether your stomach can acidify it, which bacteria live on your tongue, how you breathe, how much you move, and when you sleep.
Pharmaceutical research is now identifying this pathway as a target. That identification is welcome and the science is serious. But the pathway was never inaccessible. It was being blocked, quietly and cumulatively, by six ordinary inputs that almost nobody has been thinking about together.
The drug intervenes at the point of failure. The terrain determines whether that point is reached at all.
The question worth asking is not whether a repurposed medication might one day help. It is whether the system it acts on is being supported or obstructed by what happens in your kitchen, your bathroom cabinet, your chair, and your bedroom every single day.
Primary citation: Ariav Y, Erez A, et al. Cancer Research, 2026. Weizmann Institute of Science. DOI: 10.1158/0008-5472.CAN-26-1818.
Supporting references: Ghebremariam YT et al., Circulation, 2013, on proton pump inhibitors and ADMA elevation. Kapil V et al., Free Radical Biology and Medicine, 2013, on chlorhexidine mouthwash and nitrate reduction. Martel C et al., Journal of Clinical Investigation, 2013, on lymphatic vasculature in macrophage reverse cholesterol transport. Lundberg JO et al., on nasal nitric oxide production and autoinhalation.
This article is educational and does not constitute medical advice. Do not start, stop, or alter any prescribed medication without consulting your doctor. If you are living with a cancer diagnosis, your oncology team’s guidance takes precedence over any general terrain framework.
If you want to understand how these pathways are running in your own body, the conversation starts with a terrain assessment. Reach out here.
Mike Ndegwa | Natural Health Guide
Discover more from Mike Ndegwa | Natural Health Guide
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