Fatty liver disease has long been regarded as a metabolic disorder primarily associated with obesity, type 2 diabetes, and a sedentary lifestyle. However, growing evidence suggests that this condition extends far beyond the simple accumulation of fat in the liver. Increasingly, researchers have shown that the metabolic environment created by fatty liver disease can influence the development, progression, and even treatment response of several types of cancer. A recent study published in Nature provides an important piece of this puzzle by demonstrating that hepatic steatosis, commonly known as fatty liver disease, may promote the development of a particularly aggressive form of liver metastasis in patients with colorectal cancer.
A growing public health concern
Fatty liver disease is one of the most common liver disorders worldwide. It is estimated that approximately one in three people has some degree of fat accumulation in the liver, a prevalence that continues to rise alongside increasing rates of obesity, metabolic syndrome, and type 2 diabetes. In most cases, the disease remains asymptomatic, meaning that many individuals are unaware they have it.
However, fatty liver disease is far from a harmless condition. Numerous studies have shown that it can progress to chronic inflammation, fibrosis, cirrhosis, and even hepatocellular carcinoma. More recently, researchers have suggested that fatty liver may also alter the liver microenvironment, affecting how this organ interacts with cancer cells originating from distant tissues, such as those found in colorectal cancer.
Why is the liver such a common site for metastasis?
Colorectal cancer is one of the most common malignancies worldwide and remains a leading cause of cancer-related mortality. Although many patients can be cured when the disease is detected at an early stage, nearly half will eventually develop metastases during the course of their illness. The liver is by far the most frequent site of metastatic spread because of its direct vascular connection to the intestine through the portal circulation, which transports not only nutrients but also circulating tumor cells.
Once cancer cells reach the liver, however, they do not all behave in the same way. Some develop well-defined lesions that remain separated from the surrounding liver tissue, known as encapsulated metastases, which generally respond better to treatment and are associated with improved survival. Others exhibit a replacement growth pattern, in which tumor cells progressively infiltrate and replace normal liver tissue. This latter pattern is considerably more aggressive, more resistant to therapy, and associated with poorer clinical outcomes. For many years, the biological mechanisms underlying these distinct growth patterns remained largely unknown.
The unexpected role of fatty liver disease
The study compared patients with colorectal cancer and liver metastases from different clinical cohorts. Researchers consistently observed that individuals with fatty liver disease were significantly more likely to develop replacement-type liver metastases than patients with healthy livers. This finding was reproduced across independent patient cohorts, strengthening the evidence that hepatic steatosis may play an important role in shaping the biology of metastatic disease.
Importantly, the study went beyond simply identifying an association. By combining advanced metabolomic analyses, proteomics, and spatial profiling technologies, the investigators reconstructed the biological mechanism linking excess hepatic fat to the aggressive behavior of colorectal cancer metastases.
How cancer takes advantage of fat as fuel
Unlike normal cells, cancer cells possess remarkable metabolic flexibility that allows them to adapt to different environments. Within a fatty liver, tumor cells encounter an abundant supply of lipids that they can exploit not only as an energy source but also as signaling molecules capable of altering their biological behavior.
The study demonstrated that these excess lipids stabilize a protein called MYC, one of the best-known regulators of cancer cell growth. MYC functions as a master transcription factor, controlling the expression of hundreds of genes involved in cell proliferation, metabolism, and tumor survival.
When MYC remains stabilized for prolonged periods, cancer cells undergo profound metabolic reprogramming. One important consequence is an increase in the production of proline, an amino acid that serves as a critical building block for collagen synthesis.
Why is this important? Because collagen is one of the major structural components of the extracellular matrix, the scaffold that surrounds cells. By producing more collagen, tumor cells actively remodel their surrounding environment, creating conditions that favor tumor growth, invasion, and expansion within the liver.
The tumor microenvironment: A key player in modern cancer biology
Today, it is widely recognized that cancer progression depends not only on the genetic alterations within tumor cells but also on the tumor microenvironment—the complex network of surrounding cells, signaling molecules, and extracellular structures that support tumor development.
Fat accumulation within the liver promotes chronic inflammation, alters hepatocyte metabolism, and changes the composition of proteins and metabolites present in the tissue. Together, these alterations transform the liver into a much more permissive environment for metastatic cancer cells to survive, proliferate, and establish secondary tumors.
This concept is consistent with previous studies published in journals such as Nature Reviews Cancer, Cancer Discovery, and Nature Reviews Gastroenterology & Hepatology, which have demonstrated that obesity, chronic inflammation, and metabolic dysfunction significantly influence tumor progression and treatment response.
Could fatty liver help guide cancer treatment?
One of the most exciting findings of the study involves its potential clinical implications.
Researchers observed that patients with higher liver fat content appeared to respond better to OMO-103, an experimental MYC inhibitor currently undergoing early-phase clinical evaluation. Although these findings still require validation in larger clinical trials, they suggest that hepatic fat content could become a valuable biomarker for identifying patients most likely to benefit from MYC-targeted therapies.
This concept aligns closely with the principles of precision medicine, which recognizes that two patients with the same type of cancer may respond very differently to the same treatment. Factors such as genetics, immune status, and metabolic health may eventually help physicians personalize therapeutic decisions and improve patient outcomes.
Figure 1. Fatty liver may promote aggressive colorectal cancer liver metastasis by altering tumor cell metabolism, increasing proline synthesis, and favoring collagen-rich metastatic niches.
Can lifestyle make a difference?
An obvious question is whether improving metabolic health could reduce the risk of developing aggressive liver metastases.
At present, there is no evidence demonstrating that weight loss or reversal of fatty liver disease alone can prevent cancer progression or treat established metastases. Nevertheless, because hepatic steatosis is often reversible through healthy dietary habits, regular physical activity, and appropriate management of metabolic disorders, this possibility has become an important area of ongoing research.
The authors emphasize the need for future studies to determine whether lifestyle interventions could decrease the risk of aggressive metastatic disease or enhance responses to emerging therapies.
A discovery that may extend beyond colorectal cancer
Although this study focused specifically on colorectal cancer, researchers believe the underlying mechanism may not be exclusive to this disease. Other malignancies, including breast cancer, also exhibit different metastatic growth patterns depending on the organ involved. Likewise, organs such as the lung and brain possess unique microenvironments that may similarly influence the behavior of metastatic cancer cells.
Understanding how a patient’s metabolism interacts with the microenvironment of individual organs may become one of the most important frontiers in oncology over the coming decade.
Main reference:
Peng-Winkler, Y., Liu, X. Z., Verheul, S. M. L., Girondel, C., Igelmann, S., Rotter, S. M., Doukas, M., Liu, M., Vandekeere, A., Planque, M., Fernández-García, J., Tabariès, S., Buetas-Arcas, M., Martínez-Martín, S., Döbbe, F., Demicco, M., Vermeire, I., Theile, J., Ceuppens, J., Haesevoets, J., … Fendt, S. M. (2026). Steatosis shapes prognosis-defining liver metastasis heterogeneity in CRC. Nature, 10.1038/s41586-026-10686-2. Advance online publication. https://doi.org/10.1038/s41586-026-10686-2
Other references:
Ophoff, D., Bos, D., van Heek, T., Witteman, B. J., de Wilt, J. H. W., Popuri, K., Beg, M. F., Winkels, R. M., van Duijnhoven, F. J. B., Giovannucci, E. L., Kampman, E., & Kok, D. E. (2026). Liver fat and clinical outcomes in individuals with stage I-III colon or rectal cancer. Journal of the National Cancer Institute, 118(3), 466–475. https://doi.org/10.1093/jnci/djaf324
Yang, S., Peng, R., & Zhou, L. (2022). The impact of hepatic steatosis on outcomes of colorectal cancer patients with liver metastases: A systematic review and meta-analysis. Frontiers in medicine, 9, 938718. https://doi.org/10.3389/fmed.2022.938718
