The SOX9 Switch

Sanjeev Kumar, MD, PhD, a nephrologist-scientist at the Cedars-Sinai Board of Governors Regenerative Medicine Institute and the Department of Medicine at Cedars-Sinai, has been studying the role of the protein SOX9 in kidney fibrosis since his postdoctoral work at Harvard and the University of Southern California.

In a paper published in the journal Science, Kumar and colleagues identified a SOX9 switch that kidney cells activate during their attempt to self-repair or regenerate after damage. When daughter cells determine that healing is complete, the SOX9 switch turns "off." However, SOX9 stays activated in daughter cells that are unable to fully regenerate damaged tissue. These unhealed cells cause fibroproliferation.

The findings solve a longstanding mystery in organ regeneration and fibrosis: why certain damaged tissue areas heal with a scar, while others do not. Furthermore, Kumar's study found that manipulating the SOX9 switch back "off" stops fibrosis.

"Our animal studies showed that if we can deactivate the switch, we can stop or even reverse the scarring process," Kumar said. "And moreover, these cells can be restored back to full regeneration. We must now find precise therapies to deactivate the switch."

The research might also lead to new insights in diagnosing fibrosis.

"Right now, the only way we can confirm that a patient's kidneys are fibrosed is by doing a kidney biopsy," Kumar explained.

Detecting persistent SOX9 activity in a biopsy may serve as a more reliable indicator of fibrosis, he said. Ultimately, Kumar hopes to eliminate the need to biopsy at all, and his team is developing blood or urine assays that can detect the presence of molecules that appear when SOX9 stays activated.

According to Kumar, the implications of this work may extend beyond the kidneys: The SOX9 switch may also apply to fibrosis in other organs.

A study published in August in Cell Reports found a similar SOX9-mediated scarring response in the lungs, he said.

Read: New Cedars-Sinai Study Pinpoints Why Some Injured Kidneys Do Not Heal

What About Lung Fibrosis?

Fibrosis in the lungs is similarly unpredictable, said pulmonologist Peter Chen, MD, the Medallion Chair in Molecular Medicine and interim chair of the Cedars-SinaiDepartment of Medicine. When the fibrotic process continues after healing is completed, it leads to idiopathic pulmonary fibrosis (IPF), which is irreversible and fatal.

In research published in the journal Nature, Chen examined lung damage in animal models and identified age as a significant factor associated with an increased likelihood of fibrosis.

"When we infect a young mouse with flu or SARS-CoV-2, they get lung damage, but they don't develop overt fibrosis," Chen said. "Whereas when we infect older mice, they do get very robust fibrosis."

In the study, Chen's research group mapped a pathway for how the immune system can cause an abnormal repair process when a virus harms lung tissue.

"We found that immune CD8+ T-cells are an important factor preventing postinfection repair and healing," explained Chen. "And the effect of these cells on the body's ability to heal appears to increase with age."

That may be the case, Chen suggests, because over time, most people's lungs suffer multiple viral and other insults. Cumulative lung damage over a lifetime, paired with comorbidities like smoking and genetics, predisposes older adults to IPF.

Chen wants to now extend the research to identify abnormal repair processes before they lead to IPF.

"By understanding early pathways, we might be able to design better therapies to prevent or stop the progress of fibrosis," he said.

Read: Immune Cells Prevent Lung Healing After Viral Infection

Fibrosis and Cirrhosis

A third of adults worldwide suffer from metabolic dysfunction-associated steatotic liver disease (MASLD), formerly called nonalcoholic fatty liver disease. Because MASLD is often symptom-free, most people are unaware they have the disease unless and until it progresses to severe hepatic fibrosis, or cirrhosis. Hepatologists have no effective remedy for the disease at this stage.

However, in a 2024 study published in the journal Nature Communications, Shelly Lu, MD, the Women's Guild Chair in Gastroenterology and director of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai, along with a team of Cedars-Sinairesearchers, successfully halted and reversed liver fibrosis in mice.

The study examined three genes-FOXM1, MAT2A and MAT2B-and the proteins they make, and it showed that the interaction of these genes created inflammation and fibrosis. When researchers blocked the FOXM1 protein in mice with hepatic fibrosis, they observed reduced liver scarring.

"We demonstrated in our study that the expression and interaction of these three proteins increased in liver fibrosis in a feed-forward manner to further drive inflammation and fibrosis," explained Lu. "And our results suggest that blocking the activity of any one of them may be an effective treatment for this disease."