Why Targeting Acetaldehyde dehydrogenases (ALDHs) is a new therapeutic strategy for liver cancer treatment

Acetaldehyde Dehydrogenases in Liver Zonation and Liver Cancer

Acetaldehyde dehydrogenases (ALDHs) are a group of enzymes that play a crucial role in the metabolism of acetaldehyde, a toxic byproduct of alcohol and drug metabolism. These enzymes are primarily found in the liver, where they are involved in the detoxification of acetaldehyde. However, recent research has shown that ALDHs also play a role in liver zonation and liver cancer.

Liver Zonation

The liver is a highly complex organ that is divided into distinct zones based on the distribution of different cell types and metabolic functions. Liver zonation is essential for maintaining liver homeostasis and proper functioning. ALDHs have been found to be differentially expressed in different zones of the liver.

Studies have shown that ALDH1A1, a specific isoform of ALDH, is predominantly expressed in the periportal zone of the liver. This zone is responsible for detoxification processes and is exposed to higher levels of acetaldehyde due to its proximity to the portal vein. ALDH1A1 helps in the conversion of acetaldehyde into less toxic compounds, thereby protecting the liver from acetaldehyde-induced damage.

On the other hand, ALDH3A1, another isoform of ALDH, is mainly expressed in the perivenous zone of the liver. This zone is responsible for lipid metabolism and is exposed to lower levels of acetaldehyde. ALDH3A1 helps in the detoxification of acetaldehyde in this zone as well.

Liver Cancer

Liver cancer, also known as hepatocellular carcinoma (HCC), is one of the leading causes of cancer-related deaths worldwide. Chronic alcohol consumption and viral hepatitis infections are major risk factors for the development of liver cancer. ALDHs have been implicated in the pathogenesis of liver cancer.

Studies have shown that ALDH1A1 is upregulated in liver cancer cells. This upregulation is associated with increased tumor growth, invasion, and resistance to chemotherapy. ALDH1A1 promotes cancer stem cell-like properties, which contribute to tumor initiation and progression. Targeting ALDH1A1 has emerged as a potential therapeutic strategy for liver cancer treatment.

Additionally, ALDH3A1 has been found to be downregulated in liver cancer. Its decreased expression is associated with poor prognosis and reduced patient survival. ALDH3A1 acts as a tumor suppressor by inhibiting cancer cell proliferation and promoting cell differentiation. Restoring ALDH3A1 expression may have therapeutic implications for liver cancer treatment.


Acetaldehyde dehydrogenases play a crucial role in liver zonation and the development of liver cancer. Understanding the differential expression and functions of ALDHs in different liver zones can provide insights into liver physiology and disease pathogenesis. Targeting specific ALDH isoforms may offer new therapeutic opportunities for liver cancer treatment. Further research is needed to fully elucidate the complex mechanisms underlying the involvement of ALDHs in liver zonation and liver cancer.