Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic hepatopathy and a leading precursor of hepatocellular carcinoma (HCC) worldwide. Initially attributed to insulin resistance (IR)-driven metabolic imbalance, recent insights highlight a multifactorial pathogenesis involving oxidative stress (OS), chronic inflammation, and immune dysregulation. The hepatic accumulation of free fatty acids (FFAs) initiates mitochondrial dysfunction and excessive reactive oxygen species (ROS) production, culminating in lipotoxic intermediates and mitochondrial DNA damage. These damage-associated molecular patterns (DAMPs), together with gut-derived pathogen-associated molecular patterns (PAMPs), activate innate immune cells and amplify cytokine-mediated inflammation. Kupffer cell activation further exacerbates OS, while ROS-induced transcriptional pathways perpetuate inflammatory gene expression. Traditional immunity refers to the well-established dichotomy of innate and adaptive immune responses, where innate immunity provides immediate but non-specific defense, and adaptive immunity offers long-lasting, antigen-specific protection. However, a paradigm shift has occurred with the recognition of trained immunity (TI)—an adaptive-like memory response within innate immune cells that enables enhanced responses upon re-exposure to stimuli. Following non-specific antigenic stimulation, TI induces durable epigenetic and metabolic reprogramming, leading to heightened inflammatory responses and altered functional phenotypes. These rewired cells acquire the capacity to produce lipid mediators, cytokines, and matrix-modifying enzymes, reinforcing hepatic inflammation and fibrogenesis. In this context, the concept of immunometabolism has gained prominence, linking metabolic rewiring with immune dysfunction. This literature review provides an up-to-date synthesis of emerging evidence on immunometabolism and trained immunity as pathogenic drivers in MASLD. We discuss their roles in the transition from hepatic steatosis to steatohepatitis, fibrosis, and cirrhosis, and explore their contribution to the initiation and progression of MASLD-related HCC. Understanding these processes may reveal novel immunometabolic targets for therapeutic intervention.

Background/Objectives: Fonte Essenziale^®, a mineral water rich in bicarbonate, sulfate, calcium, and magnesium, has shown potential in modulating the gut–liver axis and microbiota in hepatic steatosis. However, its long-term effects on intestinal permeability (IP), systemic inflammation (SI), and oxidative stress—key factors in Metabolic dysfunction-associated steatotic liver disease (MASLD)—remain unexplored. Methods: Eighty-seven MASLD patients were randomized into two groups: group A received Fonte Essenziale^® (400 mL/day, fasting) plus a controlled nutritional regimen for 12 months, followed by a 6-month water washout; group B followed only the controlled nutritional regimen. IP markers, SI (IL-1β, IL-6, TNF-α), oxidative stress (dROMs/BAP), and clinical data (including Controlled Attenuation Parameter—CAP) were assessed at baseline (T0), 12 months (T12), and post-washout (T18). Baseline increased IP (in-IP) was defined by fecal zonulin > 110 ng/mL and serum LBPp > 10 µg/mL; improvement (im-IP) required normalization of both. A ≥30% CAP reduction indicated steatosis improvement. Results: Thirty-eight patients in group A and thirty-nine in group B completed the study. At T12, group A showed significant reductions in fecal zonulin (p: 0.0163) and serum LBPp (p < 0.0001), with increased occludin and claudin 1 (all p < 0.0001). Im-IP prevalence was higher in group A (p: 0.0037). Group A also showed significant reductions in IL-1β, TNF-α, IL-6, LPS, and dROM/BAP (all p < 0.05), especially among those with im-IP. CAP, insulin, and HDL levels improved significantly (all p < 0.0001). Multivariate analysis confirmed water intake (aOR: 2.185, p: 0.001) and im-IP achievement (aHR: 1.267, p: 0.021) as predictors of steatosis improvement. Benefits persisted at T18. Conclusions: Prolonged Fonte Essenziale^® intake improved hepatic steatosis and MASLD outcomes by modulating IP, SI, and oxidative stress. This trial has been registered on clinicaltrials.gov (NCT07211113).

Background/Objectives: In the present study, the Metabolic dysfunction-associated fatty liver disease (MAFLD) and Metabolic dysfunction-associated steatotic liver disease (MASLD) diagnostic criteria were applied to evaluate the relative performance in predicting short-term advanced fibrosis (AF) progression (AFpr) and hepatocellular carcinoma (HCC), as well as an ancillary outcome, i.e., the occurrence of acute cardiovascular events (ACEs) in steatotic liver disease (SLD) patients. Methods: We retrospectively analyzed the data stored in the University Hospital (UH)’s Official Health Documents Digitization Archive of 931 SLD patients, with a follow-up of 3 years. Based on the Body Mass Index (BMI), patients were subdivided into lean “L” (BMI < 25 kg/m²) (n = 134) and not-lean “NL” (n = 797), and, subsequently, into NL-MASLD (n = 206), NL-MASLD/MAFLD (n = 481), NL-MAFLD (n = 110), L-MASLD (n = 39), L-MASLD/MAFLD (n = 68), and L-MAFLD (n = 27). All study outcomes (AFpr, HCC, and ACE) were primarily evaluated in NL-SLD and by conducting a sub-analysis of L-SLD individuals. Results: MASLD and MAFLD criteria similarly estimated [p = 0.076] the overall 3-year risk of AF progression in NL-SLD. In the L-SLD sub-analysis, MAFLD criteria better estimated the overall 3-year risk of AF progression [p = 0.006]. Multivariate competing risk analysis (adjusted for sex, age, diabetes, steatosis, and fibrosis severity) revealed diabetes [adjusted Hazard Ratio (aHR) = 2.113, p = 0.001], high-sensitivity C-reactive protein (aHR = 1.441; p = 0.02), and Homeostatic Model Assessment for Insulin Resistance (aHR = 1.228; p = 0.03) as being associated with AF progression in L-MAFLD. Compared to MAFLD, MASLD diagnostic criteria similarly estimated the 3-year risk of HCC occurrence both in NL [HR = 1.104, C.I. 95%: 0.824–1.593, p = 0.741] and L [HR = 1.260, C.I. 95%: 0.768–2.104, p = 0.701] patients. Finally, no significant differences were reported between the MAFLD or MASLD criteria for ACE risk occurrence in all study groups. Conclusions: The MAFLD criteria better estimate the AF progression risk, limited to L-SLD patients.

The term “plastics” is an umbrella term generally referring to any material containing a high level of polymer content as an essential ingredient. Micro(nano)plastics (MNPs) are derived from the degradation of plastics, representing exogenous substances whose exposure can potentially interfere with different physiological processes. In this scenario, even considering the relative paramount detoxification role, the liver emerges as a key active organ in the relationship between plastic exposure and human disease. In industrialized countries, where plastics constitute largely diffused components of objects routinely adopted in daily/social life, including food packaging, Metabolic dysfunction-associated Steatotic Liver Disease (MASLD) represents the predominant hepatopathy and is progressively becoming the leading cause of cirrhosis and liver cancer, with an incompletely elucidated multifactorial pathogenesis. Notably, oral exposure to MNPs has been revealed to impact the gut–liver axis by influencing gut microbiota composition, gastrointestinal absorption, and, ultimately, determining hepatic accumulation. At the hepatic level, MNPs can contribute to the onset and worsening of steatosis by inducing metabolic dysfunction and inflammation. Plastics can also serve as vectors for different potentially toxic additives, with specific MNPs constituting a persistent source of release of bisphenol A (BPA), a well-recognized exogenous etiological factor contributing to MASLD genesis and worsening. Recently, exposure to MNPs and additives has demonstrated significant impacts on the immune system, oxidative stress, and metabolism. In particular, polystyrene-derived MNPs impair the mechanisms regulating hepatic lipid metabolism, simultaneously acting as antigens abnormally triggering the innate immune response. At the same time, environmental BPA exposure has been revealed to trigger trained immunity-related pathways, configuring novel pathogenetic drivers potentially promoting the progression of MASLD. The present review, after rapidly overviewing the main sources and toxicological properties of MNPs and related additives, explores plastic-related exposure’s potential implications in the genesis and progression of hepatic steatosis, highlighting the urgent need for further clarification of relative pathogenetic mechanisms.

Background: Hepatic malignancies are a major global health burden, with rising incidence, high mortality, and frequent diagnosis at advanced or unresectable stages. Although surgical resection, locoregional therapies, and systemic treatments have improved outcomes, many patients remain ineligible for curative strategies because of tumor burden, anatomical constraints, or liver dysfunction. Liver transplantation (LT) has therefore evolved from a treatment limited to selected hepatocellular carcinoma (HCC) cases within strict morphological criteria to a broader oncologic option guided by tumor biology and treatment response. This review provides an updated overview of the expanding role of LT in hepatic malignancies and the transition toward precision transplant oncology. Methods: We conducted a narrative review of current evidence on LT in HCC, cholangiocarcinoma (CCA), and colorectal liver metastases (CRLM), focusing on candidate selection, neoadjuvant strategies, molecular profiling, immunological aspects, and future perspectives. Results: In HCC, expanded criteria and bridging/downstaging strategies, including immunotherapy, have increased transplant eligibility, although concerns remain regarding rejection risk and post-transplant management. In CCA, especially perihilar disease, standardized neoadjuvant protocols followed by LT have achieved encouraging long-term survival in highly selected patients, whereas intrahepatic CCA remains investigational within prospective biomarker-driven studies. In CRLM, once considered an absolute contraindication, recent evidence supports LT in selected patients with liver-confined and biologically favorable disease, emphasizing the importance of tumor kinetics, molecular features, and response to systemic therapy. Conclusions: Integration of molecular oncology, immunology, and advanced therapies is redefining LT indications for hepatic malignancies. Future progress will depend on biomarker-driven selection, precision medicine, and multidisciplinary decision-making to optimize outcomes while addressing ethical challenges in organ allocation.