he study analyzes the cellular and molecular mechanisms underlying this relationship, as well as current challenges in diagnosis and treatment.
Dr Josep M. Llovet, head of the Translational research in hepatic oncology group at IDIBAPS; Dr Albert Gris-Oliver, researcher in the same team; and Dr Ramon Bataller, head of the Hepatology Department at Clínic and leader of the Steatohepatitis and liver transplantation group at IDIBAPS, have participated in the study.
The link between liver disease and cancer
Steatotic liver diseases —including those associated with metabolic dysfunction as well as those related to alcohol consumption— are currently one of the main and growing causes of chronic liver disease and liver cancer worldwide. They are characterized by the accumulation of fat in the liver and can progress to more advanced stages, including chronic inflammation or steatohepatitis, fibrosis and cirrhosis, ultimately leading to the development of liver tumors, mainly hepatocellular carcinoma.
The authors also highlight that metabolic risk factors and alcohol consumption often coexist and together increase the risk of cirrhosis and liver cancer.
In recent decades, the incidence of hepatocellular carcinoma has increased significantly, in parallel with the rise in risk factors such as obesity, diabetes and other metabolic disorders.
A complex process involving multiple factors
The review highlights that cancer development is driven not by a single mechanism but by a complex interplay of behavioral factors (diet, alcohol consumption and sedentary lifestyle), metabolic, immune and genetic processes. Key contributors include lipid accumulation in the liver, chronic inflammation, oxidative stress leading to DNA damage, and alterations in the immune system.
These factors create an environment that promotes tumor development and progression. The authors also emphasize that different causes of liver disease —metabolic or alcohol-related— may lead to tumors with apparently similar biological features but distinct underlying mechanisms.
A complex process involving multiple factors
The review emphasizes that progression to cancer does not depend on a single mechanism, but on a complex combination of behavioral factors (diet, alcohol consumption and sedentary lifestyle), as well as metabolic, immunological and genetic factors. Among the key elements contributing to this process are lipid accumulation in the liver, chronic inflammation, oxidative stress leading to DNA damage, and alterations in the immune system.
These factors create an environment that promotes the development and progression of the tumor. In addition, the authors underline that the different causes of liver disease —metabolic or alcohol-related— may lead to tumors with apparently similar biological characteristics, but with distinct underlying mechanisms.
The key role of the immune system and metabolism
One of the central aspects of the article is the analysis of how the immune system and metabolism interact in the development of liver cancer. The researchers highlight that the tumor microenvironment —composed of immune cells, metabolites and inflammatory factors— plays a determining role in disease progression and in the response to treatments.
In this regard, recent research has made it possible to identify tumor subtypes associated with different molecular and immunological profiles, which may be linked to patient prognosis and to the effectiveness of therapies such as immunotherapy.
Challenges in diagnosis and treatment
The study also highlights that liver cancer associated with these diseases is often diagnosed at advanced stages. In particular, a significant proportion of tumors linked to metabolic alterations may arise in individuals without cirrhosis, who are usually not included in surveillance programs, making early detection more difficult.
The authors further note that there is increasing evidence that tumors associated with steatotic liver diseases may present distinct biological characteristics, which can influence their response to treatments such as immunotherapy.
In addition, the coexistence of underlying liver disease limits therapeutic options, as liver function is often impaired. In this context, the authors emphasize the need to improve early detection strategies, identify more precise biomarkers, and develop treatments tailored to the characteristics of each patient’s liver disease.
The study also points to the potential of emerging approaches, such as multi-omics data analysis and the use of artificial intelligence tools, to advance towards more personalized medicine.
Towards more precise and personalized research
The review concludes that it is necessary to advance towards a more detailed understanding of the different causes of liver cancer, particularly in relation to steatotic liver diseases, as well as the specific mechanisms involved in each patient.
The authors emphasize that liver cancer associated with these conditions should not be considered a single disease, but rather a group of biologically distinct subtypes that will require specific prevention and treatment strategies for these patients.
Therefore, a more tailored and patient-adapted approach could improve prognosis and help reduce the overall burden of this disease.
Study reference:
Rahbari M, Gris-Oliver A, Ramadori P, Aicher D, Sia D, Malek NP, Loomba R, Bataller R, Llovet JM, Heikenwälder M. The versatile interplay between steatotic liver disease and liver cancer. Nat Rev Cancer. 2026 Jun;26(6):415-436. doi: 10.1038/s41568-026-00918-y. Epub 2026 Apr 14.
