In humans, the bioactivity of polyphenols is highly dependent on dose intake and their interactions with the gastrointestinal tract and gut microbiota, which metabolize polyphenols into bioactive or inactive derivatives. Polyphenols are only partially absorbed in the small intestine, where enzymatic hydrolysis releases aglycone forms that may cross the gut barrier. A significant proportion of polyphenols escapes absorption and reaches the colon, where resident microbes convert them into simpler phenolic metabolites. Such molecules are often more bioavailable than the parent compounds and can enter systemic circulation, leading to distant effects. Although higher polyphenol consumption has been associated with preventive and therapeutic outcomes, even low intake or poor intestinal absorption may still confer benefits, as polyphenols in the colon can positively modulate gut microbiota composition and function, contributing to favorable shifts in the microbial metabolome. These interactions can influence host metabolic, immune, and neurological pathways, particularly through the gut–liver–brain axis. To provide a comprehensive understanding of these relationships, this review examines the dose-related activity of polyphenols, their microbiota-mediated biotransformation, their bioavailability, and the health effects of their metabolites, while also presenting a comparative overview of key studies in the field. We underscore the importance of integrating microbiome and polyphenol research to recapitulate and contextualize the health benefits of dietary polyphenols.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a leading driver of hepatocellular carcinoma (HCC) worldwide. A substantial proportion of MASLD-related HCC arises in the noncirrhotic liver, highlighting critical gaps in current surveillance strategies that rely primarily on fibrosis stage to define risk. Although the annual incidence of HCC in noncirrhotic MASLD is low and does not justify universal surveillance, the extraordinary global prevalence of MASLD translates into a considerable absolute burden of cancer. Accumulating evidence demonstrates that HCC risk in MASLD is modulated not only by histologic severity but also by metabolic comorbidities, particularly type 2 diabetes mellitus, which can significantly amplify cancer risk even in pre-cirrhotic stages. From both clinical and health economic perspectives, these observations underscore the need for more complex and targeted surveillance approaches. This review synthesizes current epidemiologic data, metabolic and histologic modifiers of HCC risk, emerging biomarkers, and predictive models in MASLD, with a focus on noncirrhotic disease. We discuss how integrated, precision-based risk assessment may identify high-risk MASLD subgroups and enable targeted, cost-effective surveillance strategies to mitigate the growing burden of MASLD-associated HCC.