Chinese Medical Journal review highlights senescence’s dual role in liver disease and emerging therapies

Cellular senescence is a process where cells permanently stop dividing in response to various stressors such as DNA damage. Initially, senescence acts as a protective mechanism, preventing the proliferation of potentially cancerous cells. However, over time, the accumulation of senescent cells can have detrimental effects, particularly in the liver. In the liver, senescence impacts key cell types including hepatocytes, liver sinusoidal endothelial cells, and Kupffer cells, and contributes to chronic liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). While senescence can provide protective effects in the early stages of liver disease, its continued presence exacerbates inflammation and fibrosis, worsening disease progression.

In light of these issues, a team of researchers led by Dr. Lin Wang from the Department of Hepatobiliary Surgery at Xi-Jing Hospital in China, conducted a study to examine the dual role of senescence in liver health. Their review article was published online on 16 December 2024 and released in Volume 137, Issue 24 of the Chinese Medical Journal on 20 December 2024.

Senescence impacts several vital liver cells, including hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells. When cells become senescent, they release inflammatory molecules known as the senescence-associated secretory phenotype (SASP). These molecules disrupt the surrounding liver environment, causing inflammation and tissue damage. While senescence initially serves as a protective mechanism to halt the growth of potentially cancerous cells, prolonged senescence contributes to chronic liver conditions such as metabolic dysfunction-associated steatohepatitis (MASH) and HCC, the most common type of liver cancer.

The study revealed that markers of senescence, including p16 and p21, are elevated in MASH, contributing to mitochondrial dysfunction, oxidative stress, and liver dysfunction. "Under physiological conditions, senescence aids organ repair and regeneration, but its accumulation due to aging or pathological stress significantly contributes to liver diseases," said Dr. Lee, the lead author of the study. The researchers highlight that, in chronic liver diseases like MASH, senescent cells promote fat buildup and inflammation, creating a damaging feedback loop that accelerates liver dysfunction.

Chronic inflammation driven by senescent cells fosters an environment conducive to cancer development. The study notes that immune cells often fail to effectively clear these senescent cells, allowing them to persist and drive cancerous changes. As Dr. Lee further emphasizes, “Recent studies have also linked hepatocyte senescence to liver cancer, highlighting the importance of studying these mechanisms.”

Despite these challenges, the study also discusses promising treatments known as senolytic therapies, which aim to selectively eliminate senescent cells while preserving healthy tissue. Drugs such as dasatinib and quercetin have shown potential in preclinical trials. “The first human trial of senolytic therapy, specifically using the dasatinib and quercetin combination, is currently underway,” said Dr. Lee. If successful, these therapies could revolutionize how liver diseases are treated by targeting the root causes of inflammation and fibrosis.

However, senolytic therapies are not without their challenges. The safety and long-term effects of these treatments remain uncertain, and their effectiveness may vary depending on the type and stage of liver disease. The study stresses the need for precision medicine, where treatments are tailored to an individual’s unique condition. “Understanding what triggers senescence and how it affects different liver cell types will be crucial to developing personalized approaches,” noted Dr. Lee.

As research continues, the dual role of senescence in liver health offers both challenges and opportunities. While senescence acts as a protective mechanism in some cases, it can also cause significant harm in others. The researchers emphasize the need for further studies to refine senolytic therapies and explore additional interventions that may enhance the liver’s natural regenerative capacity.

This research highlights the complexity of senescence in liver health. By presenting senescence as both a protective mechanism and a cause of liver disease, the study opens new avenues for understanding how to harness its benefits while mitigating its harmful effects. As research on senescence evolves, it holds the promise of transforming the treatment of chronic liver diseases, offering hope for patients struggling with these conditions.

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Reference

Titles of original papers: Navigating the complex role of senescence in liver disease

Journal: Chinese Medical Journal

DOI: 10.1097/CM9.0000000000003439