This thesis explores the interplay between maternal obesity, the gut microbiome, and hepatocellular carcinoma (HCC), linking mechanistic insights from preclinical research to clinical applications in hepatobiliary surgery and transplantation. The central theme is that maternal obesity not only affects the health of affected women but also imprints a transgenerational vulnerability to chronic liver disease and cancer in their offspring. Using transcriptomic meta-analyses and mouse models, we demonstrated that maternal obesity disrupts key transcriptional pathways in the offspring, predisposing them to steatosis, fibrosis, and inflammation, hallmarks of chronic liver disease. Importantly, we identified the altered gut microbiome as a decisive mediator of this risk. Offspring of obese mothers carried a dysbiotic microbiome that persisted into adulthood and increased susceptibility to the development of HCC. Microbial restoration normalized cancer risk, positioning the microbiome as both transmission vector and therapeutic target.

In parallel, clinical studies included in this thesis contextualize these findings in the broader field of surgery and transplant oncology. A systematic review highlighted the long-term oncological risks of pedicle clamping during liver resection, underscoring how surgical technique influences cancer recurrence. A review of transplant oncology indications synthesized the rapid expansion of liver transplantation for oncological indications, moving from restrictive Milan criteria for HCC to biology-driven frameworks now being tested for cholangiocarcinoma and colorectal liver metastases. Finally, in a large international cohort, we investigated the safety of immune checkpoint inhibitors prior to liver transplantation and defined a 50-day washout period as a critical threshold to reduce the risk of rejection without compromising recurrence outcomes.

The included studies form a continuum from prenatal origins of liver disease, to surgical and transplant strategies once HCC has developed, and to the integration of emerging systemic therapies such as immunotherapy into multimodal treatment regiments. These studies provide preclinical evidence for microbiome-targeted prevention, refine surgical and transplant decision-making, and generate important data to safely combine ICIs with transplantation.