Srinagar, Sep 12: A fresh scientific review published this week in the leading journal Gut elucidates how a dangerous cascade turns common metabolic liver disease into cancer.
The researchers led by Kashmir’s noted endocrinologist Muhammad Shafi Kuchay highlight how genetic risks and metabolic stress make liver cells vulnerable to a form of iron-driven cell death called ferroptosis.
The team, that included Francisco Javier Cubero and Bruno Ramos-Molina led by Dr Kuchay demonstrated how the dying liver cells spark a self-reinforcing wave of inflammation that drives fibrosis (scarring).
It raises the risk of hepatocellular carcinoma (HCC), the most common liver cancer.
Speaking to Greater Kashmir, Dr Kuchay said for decades, doctors and scientists had watched a quiet trend sweep across the world: the rise of fatty liver disease, driven by modern diets, lack of movement, and diabetes.
He said millions of people live with simple fat buildup in their livers, a significant number of individuals cross a dangerous line into a severe, inflamed condition known as MASH.
“This advanced stage can lead to permanent scarring, long-term liver failure, and even cancer, yet the exact spark that sets off this destructive fire has remained a puzzle. Not anymore,” he said.
Dr Kuchay said when too much fat and iron build up inside the liver, they interact with specific fats in cell walls to create a destructive chain reaction. This reaction damages the outer shell of liver cells, he said.
Taking one more layer off the condition, he said, “Normally, the body has natural chemical shields and antioxidants that clean up this kind of damage. Under chronic stress, however, these defense systems completely wear out and collapse.”
The work arrives as metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD) and its progressive form metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) continue to rise and compromise life and health of millions.
Driven by obesity, type 2 diabetes, and metabolic syndrome, MASH is already a major cause of cirrhosis.
Dr Kuchay said to understand the process better, one can think of liver cells as factories processing fats and sugars.
In people with genetic predispositions plus excess metabolic stress, these cells become overloaded with bad fats and labile iron.
This triggers a kind of “rusting” of cell membranes, and these membranes tend to rupture.
When these membranes tear, they spill danger signals and toxic lipid byproducts.
Now, these signals activate resident liver immune cells (Kupffer cells) and recruit more inflammatory macrophages.
The immune response pumps out cytokines that further weaken the cells’ antioxidant defenses.
A vicious cycle of more cell death sets off, leading to more inflammation.
“Over time, this chronic injury activates hepatic stellate cells and cause progressive scarring (fibrosis),” Dr Kuchay said. “These changes increase the chance of mutations that can lead to liver cancer.”
The new paper breaks the process into three major stages – upstream genetic and transcriptomic priming, a core self-amplifying ferroptosis–immune crosstalk loop, and downstream fibrosis plus oncogenic priming.
These culminate in HCC.
Lifestyle measures that improve metabolic health (weight loss, better blood sugar control, reduced alcohol) remain foundational for prevention.
These reduce the upstream stress that primes cells for ferroptosis.
MASH often develops silently for years, and gets discovered in advanced disease stage when cirrhosis or cancer appears.
No ferroptosis-specific drug is yet approved for MASH.
The Gut study has been lauded by medical and research fraternity globally.
Dr Kuchay and his team has received applause for the breakthrough findings from scientists from various medical universities.
