The surprising discovery that "liver cells cannot be necrotic" points to a new direction in the treatment of liver disease

The researchers at WEHI found that common liver disease is not caused by the death of inflammatory cells as previously thought, which solves the long-standing controversy in gastroenterology and points in a new direction
for treatment.
The research team studied liver diseases that affect billions of people worldwide, including non-alcoholic fatty liver disease and hepatitis B, to understand what drives the development of
these diseases.
Their unexpected discovery — that liver cells cannot experience cell death in an inflammatory form called "necrosis" — addresses a key open question in the field and will help guide the development of
new therapeutic interventions.

• The researchers at WEHI revealed for the first time that an important type of liver cells cannot undergo necrosis, thus eliminating this type of cell death as a driver of common liver disease

• This astonishing finding sheds light on the role and relevance of necrosis in non-cancerous liver disease, which affects billions of people worldwide

• The findings will help provide new strategies for developing treatments for these liver diseases

These findings, published in the journal Gastroenterology, clarify the controversial role of necrosis in the progression of liver pathology and provide fundamental insights
to guide future preclinical and clinical research in new directions 。 The study was led by lead researcher Dr Marcel Doerflinger, former WEHI PhD researcher Dr Simon Preston and lead researcher Professor Marc Pellegrini, and collaborated
with researchers from the Peter Doherty Institute of Infection and Immunology and the University of Queensland.

Liver damage

Liver disease is a major and growing burden on global health
.
Non-alcoholic fatty liver disease is the most common liver disease, affecting more than 30% of the world's population, and more than 296 million people worldwide are infected with hepatitis
B.
So far, researchers believe that necrosis is crucial in the progression of
these diseases.
However, it is unclear whether this pattern of cell death occurs in liver cells or in immune cells that invade the liver due to infection or diet-related damage
.

Study leader Dr Doerflinger said: "We tried to address this research gap and determine the role and relevance of
necrosis in common liver diseases.
"

The researchers used several preclinical genetic models of liver disease, including non-alcoholic fatty liver disease and its advanced forms, non-alcoholic steatohepatitis, and hepatitis
B.
The team removed key genes needed for necrosis from liver cells known as "liver cells" to see the effects on
disease development.
They found that deleting these genes had little effect, and disease progression proved comparable
to normal liver cells.
This suggests that necrosis is not associated
with the development of these liver pathologies.

Dr Doerflinger said: "The liver is an important organ because it plays an important role
in the body's metabolism and detoxification.
It's unclear why necrosis in liver tissue is suppressed, but we speculate that this may be because the liver is constantly bathed in necrotic signals, such as gut microbial products, so limiting necrosis may protect the liver from excessive inflammation
.
”

Molecular mechanisms

The study also revealed the molecular mechanisms
that cause hepatocytes to fail to develop necrosis.
After genetic analysis of human liver tissue samples, the team found that liver cells could not produce RIPK3
, a protein critical for necrosis.
The production of the RIPK3 protein is limited at the genetic level, and the RIPK3 gene is blocked
by an epigenetic modification called "methylation.
"

"Methylation acts as a gene blockade, preventing the body's protein-producing mechanisms from binding to DNA and producing the RIPK3 protein," Dr.
Doerflinger said
.
"Therefore, without this necessary protein to perform its necrotic function, the cell death pathway cannot be initiated
.
"

Dr.
Doerflinger said the momentum of RIPK3 inhibitors has been growing to potentially treat liver disease, but their potential clinical applications are limited
by a lack of fundamental insights.
"These findings are core data to address many unsolved problems in the field and will guide future preclinical trials and clinical studies
in this direction.
"

Simon P.
Preston, Michael D.
Stutz, Cody C.
Allison, Ueli Nachbur, Quentin Gouil, Bang Manh Tran, Valerie Duvivier, Philip Arandjelovic, James P.
Cooney, Liana Mackiewicz, Yanxiang Meng, Jan Schaefer, Stefanie M.
Bader, Hongke Peng, Zina Valaydon, Pravin Rajasekaran, Charlie Jennison, Sash Lopaticki, Ann Farrell, Marno Ryan, Jess Howell, Catherine Croagh, Denuja Karunakaran, Carole Schuster-Klein, James M.
Murphy, Theodora Fifis, Christopher Christophi, Elizabeth Vincan, Marnie E.
Blewitt, Alexander Thompson, Justin A.
Boddey, Marcel Doerflinger, Marc Pellegrini.
Epigenetic Silencing of RIPK3 in Hepatocytes Prevents MLKL-mediated Necroptosis From Contributing to Liver Pathologies.
Gastroenterology, 2022