Study links loss of nuclear PHB1 to alcohol-related liver injury

Researchers at Cedars-Sinai and Spain’s CIC bioGUNE have identified a molecular change that appears to help drive alcohol-associated liver injury and make the liver more vulnerable to colon cancer spread in experimental models, according to a study published Oct. 6 in The Journal of Clinical Investigation.

The work centers on prohibitin 1, or PHB1, a protein that helps protect cells. The researchers found that in alcohol-associated liver disease, PHB1 was depleted in the cell nucleus and cytosol in human samples, mouse models, and laboratory cell models, while mitochondrial PHB1 was largely preserved even though mitochondrial mass fell. The authors said that loss of PHB1 from the nucleus, rather than an overall disappearance of the protein from every part of the cell, was a key event linked to liver damage.

Alcohol-associated liver disease, often shortened to ALD, is a major cause of illness and death worldwide. The paper notes that ALD is also associated with a higher incidence of colorectal liver metastasis, meaning cancer cells from the colon or rectum spreading to the liver. The role of PHB1 in that connection had been unclear.

The team reported that alcohol exposure promoted the export of PHB1 out of the nucleus through a pathway mediated by CRM1, a protein involved in moving cargo from the nucleus into the cytoplasm. To test whether stopping that movement could protect the liver, the researchers used a peptide designed to block the nuclear export signal of PHB1. In the study, that approach kept PHB1 in the nucleus and reduced liver injury in experimental ALD models. It also lessened the liver’s susceptibility to colon cancer metastasis in ALD-related mouse models.

According to the paper, preserving nuclear PHB1 helped prevent the depletion of nuclear methionine adenosyltransferase α1, or MATα1, another protein involved in liver health. The treatment also lowered oxidative stress and reduced the induction of matrix metalloproteinase 7, known as MMP-7, along with multiple oncogenes that can support tumor growth and spread.

The research combined several types of analysis. The group used single-nucleus RNA sequencing on livers from mice fed the National Institute on Alcohol Abuse and Alcoholism diet, a standard model for studying alcohol-related liver injury. They also used spatial transcriptomics in mice with alcohol-associated liver disease and colorectal liver metastasis. Those tools allowed the researchers to examine how gene activity changed across different liver cell populations and tissue regions.

The authors said the data showed that keeping PHB1 in the nucleus reduced alcohol-related metabolic stress and oncogenic stress, dampened inflammatory and fibrosis-related responses, and reshaped an immunosuppressive environment that can favor tumor growth. In the metastasis model, the liver microenvironment became less supportive of cancer cell establishment and expansion when the PHB1-targeting peptide was used.

The study was led by investigators including Jyoti Chhimwal, Sonal Sinha, Jina Kim, Mario Alba, Lucía Barbier-Torres, Jiaohong Wang, Heping Yang, Youngyi Lim, Ramachandran Murali, Maria Lauda Tomasi, Sungyong You, José M. Mato, and Shelly C. Lu. The work was conducted at Cedars-Sinai in Los Angeles and CIC bioGUNE in Spain.

The findings add detail to how alcohol can damage the liver at the cellular level. Rather than focusing only on broad inflammation or fat buildup, the paper points to a specific shift in where a protective protein is located inside the cell. That distinction may matter because the mitochondrial pool of PHB1 remained in place, while the nuclear pool was selectively lost. The results suggest that the location of the protein, not just its total amount, may influence whether liver cells move toward injury and whether the organ becomes more permissive to metastasis.

The researchers describe nuclear PHB1 depletion as both a driver of alcohol-associated liver disease and a potential therapeutic target. Still, the work remains preclinical. Although it included human, mouse, and cell-based evidence, the intervention tested in the study was not evaluated as a treatment in patients. The paper does not show that blocking PHB1 export can prevent or reverse liver disease in people, nor does it establish a new therapy for cancer metastasis in clinical practice.

That caution is likely to be important beyond liver research. For producers of beer, wine, spirits, and other alcoholic beverages, the study could add to the body of biological evidence cited in public health debates about alcohol-related harm. At the same time, the findings do not change clinical guidance on their own and do not prove that a drug strategy based on PHB1 will work in humans.

The paper was published as an open-access article in The Journal of Clinical Investigation under the DOI 10.1172/JCI206235. The authors said future work will need to determine whether the same mechanism can be safely targeted in patients with alcohol-associated liver disease and whether it could have a role in reducing the risk of liver metastasis in people with colorectal cancer.