investigators linked higher coffee consumption with lower risk of cirrhosis, liver cancer and liver-related death.

“Previous studies suggested that coffee might benefit the liver, but most were smaller or looked at only one piece of the puzzle,” said hepatologist Hyunseok Kim, MD, MPH, PhD, assistant professor of Medicine at Cedars-Sinai and corresponding author of the study. “We followed hundreds of thousands of people for more than a decade and looked at their health outcomes along with liver MRI scans and blood protein analyses. Together, those findings help explain the biological mechanisms behind coffee’s association with better liver health.”

A Cedars-Sinai study of more than 355,000 adults found that drinking coffee was associated with lower risks of cirrhosis, liver cancer and liver-related death. The investigators analyzed data from 354,957 UK Biobank participants who did not have cirrhosis or liver cancer at the start of the study. Over a median follow-up of 13 years, researchers tracked new diagnoses of cirrhosis, liver cancer and liver-related death through linked health records.

Compared with people who did not drink coffee, those who drank five or more cups of coffee a day had a 32% lower risk of cirrhosis, a 47% lower risk of liver cancer and a 42% lower risk of liver-related death. Participants who drank more coffee also had lower levels of liver fat, liver iron, fibrosis and liver inflammation in MRI scans. And coffee drinkers’ blood tests showed higher levels of proteins tied to healthy liver function and lower levels of proteins linked to scarring and inflammation.

While liver health risk decreased as coffee consumption increased, researchers noted that benefits were seen even at one to two cups per day and appeared strongest around three to four cups per day. They emphasized that while the highest intake group (five or more cups daily) showed benefit, they would not recommend increasing consumption to that level specifically.

Similar protective associations were observed for caffeinated and decaffeinated coffee, suggesting that caffeine itself is unlikely to be the only active component, and that other naturally occurring compounds in coffee may contribute to the benefits. Because the study was observational, investigators noted it does not prove that coffee itself prevents liver disease. And they emphasized that coffee should complement—not replace—established strategies for preventing liver disease.

“Our findings support moderate coffee consumption for people who already enjoy and tolerate it well,” said study senior author Ju Dong Yang, MD, medical director of the Liver Cancer Program at Cedars-Sinai. “However, we would not recommend that someone begin drinking coffee solely for liver protection based on this study alone. Prevention should continue to focus on maintaining a healthy weight, limiting alcohol, exercising regularly, and managing blood sugar, blood pressure and cholesterol.”

Because caffeine isn’t appropriate for everyone, people with uncontrolled high blood pressure, certain heart rhythm disorders, severe anxiety, insomnia or other conditions that require limiting caffeine should consult their healthcare provider before increasing their coffee consumption.

“The next step in our research is to identify the specific compounds in coffee that are responsible for these liver-protective associations,” said study author Shelly Lu, MD, the Women’s Guild Chair in Gastroenterology and director of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai. “Our findings point to biological pathways involving inflammation and scarring and highlight molecular targets that future research can explore to better understand how coffee may influence liver health and who stands to benefit the most.”

Additional Cedars-Sinai authors include Yufeng Wang, Abdelrahman M. Attia, Minsun Kwak, Seungwon Burm, Derin Celtik, Daniel Legaspi, Osama Khattab, Naomy Kim, Beza M. Mengistu, Kelsey N. Larios, Walid Ayoub, Alexandar Kuo, Paul Martin, Aarshi Vipani, Yun Wang, Debiao Li and Stephen Pandol.

Other authors include Mohammad Saeid Rezaee-Zavareh, David Sooik Kim and Suthat Liangpunsakul.

Conflicts of Interest: Ju Dong Yang reports the following conflicts of interest: consulting service for AstraZeneca, Eisai, Exact Sciences, and Fujifilm Medical Sciences.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

Alcohol‐associated liver disease, which is caused by chronic alcohol use, can lead to inflammation and scarring of the liver. In severe cases it can lead to liver failure, with some patients requiring a liver transplant. The condition accounts for nearly half of the liver-disease-related deaths in the U.S., according to the National Institutes of Health.

“We do not have effective therapies for alcohol‐associated liver disease,” said Shelly Lu, MD, the Women's Guild Chair in Gastroenterology and director of the Karsh Division of Gastroenterology and Hepatology. “Abstaining from alcohol can arrest this condition but this is often difficult to achieve. To save lives, we need to target drivers of alcohol-associated liver disease that promote inflammation and scarring. ”

Lu is co-corresponding author of a study, published in Hepatology, which connected a protein called FOXM1 with scarring and inflammation in alcohol‐associated liver disease. Another recent Cedars-Sinai study, published in Science Advances, showed that alcohol caused an enzyme known as SRC to alter the liver’s immune responses.

In Lu’s study, investigators examined alcohol-exposed human liver tissue samples and cells, and those of laboratory mice. They found that the FOXM1 protein controlled a network of genes and proteins that worked together to cause liver scarring and inflammation. FOXM1 is known to be involved in multiple liver diseases, including cancer. When the investigators suppressed the action of FOXM1, liver scarring was reversed.

“We found that FOXM1 is a key regulator of alcohol-associated liver disease progression and represents a promising target for therapeutic intervention,” Lu said.

The Science Advances study demonstrated how alcohol exposure—through the action of the enzyme SRC and the protein called UBC9—triggered inflammation and immune changes in the liver. When investigators used gene editing or enzymes to block SRC activity,  inflammation was reduced.

“The strong effect of enzymes suggests the possibility of therapeutic targets against alcohol‐associated liver disease,” said Maria Lauda Tomasi, PhD, associate professor of Medicine and Biomedical Sciences at Cedars-Sinai and the study’s co-corresponding author.

The findings also highlight UBC9 as a key regulator of the immune response, which could have implications beyond the liver for cancer and other inflammatory diseases, Tomasi said.

“These rigorous studies contribute greatly to our understanding of alcohol‐associated liver disease,” said David E. Cohen, MD, PhD, chair of the Department of Medicine. “The findings could open new pathways for the development of urgently needed treatments.”

Other Cedars-Sinai authors of the Hepatology study include Bing Yang, Liqing Lu, Jiaohong Wang, Lucía Barbier-Torres, Jing Zhang, Jyoti Chhimwal, Sonal Sinha, Brent Beadel, Guo Zhang, Takashi Tsuchiya, Maria Lauda Tomasi and Heping Yang. The other author was Ting Liu.

Funding: This work was supported by NIH grant R01AA026759 (Shelly C. Lu, Heping Yang, and Maria Lauda Tomasi).

Other Cedars-Sinai authors of the Science Advances study include Swati Chandla, Youngyi Lim, Andrea Floris, Michael Mazarei, Xi Yang, Takashi Tsuchiya, Manisha Dagar, Alfonso Darmawan, Monica Justo, Ramachandran Murali, Alexandra Gangi, Nirmala Mavila and Komal Ramani. The other author was Ivan Tomasi.

Funding: This work was supported by the National Institutes of Health, grant 

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

Liver fibrosis can be triggered by many factors, including viruses that cause hepatitis (infection and inflammation in the liver), long-term alcohol use or some metabolic disorders. Because it produces few or no symptoms at first, the condition typically progresses slowly for years, going undetected until it has caused serious organ damage. At that stage, liver transplantation may be the only effective treatment. The ability to undo the scarring would be a major breakthrough for patient care.

In their study, published in the peer-reviewed journal Nature Communications, Cedars-Sinai investigators examined three genes and the proteins that they made. One of them, FOXM1, is known to cause liver cancer, inflammation and fibrosis when it becomes overactive in hepatocytes, a type of liver cell. The two other genes, MAT2A and MAT2B, are required to activate another type of cell, hepatic stellate cells, which plays a key role in liver fibrosis. The study demonstrated that the proteins coded by these three genes interact and that all three are needed to produce liver fibrosis.

“We discovered that these proteins ‘talk’ with each other inside liver cells,” said Shelly Lu, MD, director of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai and corresponding author of the study. “They even influence nearby cells through extracellular vesicles—fat molecules filled with genetic fragments, proteins and other biological materials that act as messengers between cells. Working together, that is how these proteins stimulate each other, driving liver inflammation and fibrosis.”

These discoveries raised the possibility that inactivating just one of the three proteins might block liver fibrosis. To test that theory, the team induced liver inflammation and fibrosis in laboratory mice and treated them with a substance known as FDI-6 that blocks the FOXM1 protein. In a series of experiments, they showed that FDI-6 could prevent liver fibrosis from developing, halt further progression and even reverse the condition, resulting in the scarring disappearing.

Although both mice and humans have all three genes, and these genes also are more highly expressed in human liver fibrosis and cirrhosis, the study did not prove that a similar treatment would work in patients with liver fibrosis. Reaching that conclusion would require additional research and testing, Lu said. 

“What we achieved was to unveil the axis of FOXM1, MAT2A and MAT2B as a potential target for developing drugs to treat liver fibrosis,” Lu said. “Our findings suggest that blocking any of these proteins might be useful in treating this condition.”

Peter Chen, MD, professor of Medicine, the Medallion Chair in Molecular Medicine and interim chair of the Cedars-Sinai Department of Medicine, said, “This highly original study significantly advances our understanding of an insidious condition that too often leaves patients and doctors with few treatment options. It is emblematic of Cedars-Sinai’s innovative scientific work.”

Other Cedars-Sinai authors include Bing Yang, Liqing Lu, Ting Xiong, Wei Fan, Jiaohong Wang, Lucía Barbier-Torres, Jyoti Chhimwal, Sonal Sinha, Takashi Tsuchiya, Nirmala Mavila, Maria Lauda Tomasi, DuoYao Cao, Jing Zhang, Hui Peng, Komal Ramani, Jenny Han, Ekihiro Seki and Heping Yang. Additional authors include Jose M. Mato, Ting Liu, Xi Yang and Vladimir V. Kalinichenko.

Funding was provided by the National Institutes of Health grant P01CA233452 to S.C. Lu, H. Yang and E. Seki; Plan Nacional of I + D SAF2017-88041-R to J.M. Mato; and the National Natural Science Foundation of China 82070632 to Liu T.

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