Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition that affects 25% of the world’s population. There is a clear difference in both geographical distribution and sex in childbearing age. These differences are reduced when women become older and senescence begins. The factors that affect the likelihood of developing NAFLD in a premenopausal woman are an imbalance of sex hormones (especially in estradiol and androgen), microbiome dysregulation, insulin resistance, early menarche, the length of time that the woman breastfeeds for and polycystic ovarian syndrome (PCOS). The aim of this review is to identify various physical ailments that may not appear to be serious to young women but that then affect the onset of NAFLD in perimenopause and can degenerate into NASH. These conditions should also be considered in future clinical management, as well as in research opportunities, in order to customize the monitoring and treatment of NAFLD, considering gender medicine for those women who had early metabolic symptoms that were not considered to be significant at the time.

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition characterized from hypertriglyceridemia and hepatic fat accumulation, in the absence of alcohol intake. NAFLD starts as steatosis (NAFL), and the continued injury relative to the toxic fat induces inflammation, steatohepatitis (NASH), and HCC. One of the factors determining liver degeneration during the evolution of NAFLD is a modification of Wnt/Frizzled (FZD) signaling. In particular, an inhibition of Wnt signaling and an overexpression of a specific FZD receptor protein, namely, the FZD7, have been observed in NAFLD. Actually, the prognosis and the follow-up of NAFLD is not easy, and the liver biopsy is the gold standard for an accurate detection of liver fibrosis. In this study, the modulation of the FZD7 expression levels in plasma-derived exosomes of NAFLD-affected patients, before and after specific lifestyle interventions, were experimentally evaluated by Western blotting analysis. The experimental data were analyzed by an accurate statistical study that indicated, in the exosomes derived from plasma of NAFLD patients with moderate or severe steatosis, an average expression level of FZD7 that was significantly higher than healthy subjects at baseline; conversely, the values were normalized after 90 days of specific lifestyle interventions. The overall results suggested that the FZD7 delivered by exosomes represents a good candidate as a new and effective biomarker for diagnosis and prognosis of NAFLD.

Plasmonic nanostructures, featuring near infrared (NIR)-absorption, are rising as efficient nanosystems for in vitro photothermal (PT) studies and in vivo PT treatment of cancer diseases. Among the different materials, new plasmonic nanostructures based on Cu_2−xS nanocrystals (NCs) are emerging as valuable alternatives to Au nanorods, nanostars and nanoshells, largely exploited as NIR absorbing nanoheaters. Even though Cu_2−xS plasmonic properties are not linked to geometry, the role played by their size, shape and surface chemistry is expected to be fundamental for an efficient PT process. Here, Cu_2−xS NCs coated with a hydrophilic mesoporous silica shell (MSS) are synthesized by solution-phase strategies, tuning the core geometry, MSS thickness and texture. Besides their loading capability, the silica shell has been widely reported to provide a more robust plasmonic core protection than organic molecular/polymeric coatings, and improved heat flow from the NC to the environment due to a reduced interfacial thermal resistance and direct electron–phonon coupling through the interface. Systematic structural and morphological analysis of the core-shell nanoparticles and an in-depth thermoplasmonic characterization by using a pump beam 808 nm laser, are carried out. The results suggest that large triangular nanoplates (NPLs) coated by a few tens of nanometers thick MSS, show good photostability under laser light irradiation and provide a temperature increase above 38 °C and a 20% PT efficiency upon short irradiation time (60 s) at 6 W/cm² power density.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely related to some metabolic disorders, such as central obesity and type 2 diabetes (T2D). Glucagon-like peptide 1 receptor agonists (GLP-1RAs), such as semaglutide, may have therapeutic roles in MASLD associated with T2D. This study aims to investigate the molecular mechanisms underlying the effectiveness of semaglutide on MASLD in terms of progression from liver steatosis to fibrosis. We characterized exosomes from ten patients with type 2 diabetes (T2D) before (T0) and after 12 months (T12) of treatment with once-weekly subcutaneous semaglutide. Six of ten patients were considered responders to therapy (R) based on MASLD severity downgrading by at least one class according to a validated ultrasonographic (US) score. Normal hepatocytes (HEPA-RG) and stellate (LX-2) cells were challenged with exosomes from R and NR patients, isolated before and after 12 months of therapy. Exosomes from both R and NR patients isolated at T0 significantly affected LX-2 viability. After 12 months of treatment, only those isolated from R patients restored cell viability, whereas those from NR patients did not. No effects were observed on HEPA-RG cells. Exosomes at T12 from R but not from NR patients significantly decreased the production of α-SMA, a marker of LX-2 activation, a liver stellate cell model, and ph-SMAD2 and CTGF, involved in fibrosis processes. TGF-β1 was not modulated by the exosomes of R and NR patients. As a downstream effect, Vimentin, Collagen 1A1, and Fibronectin extracellular matrix components were also downregulated, as measured by droplets digital PCR. In conclusion, these results shed light on the potential effectiveness of semaglutide in improving liver fibrosis in MASLD.

Exosomes produced by hepatocytes upon lipotoxic insult play a relevant role in pathogenesis of nonalcoholic fatty liver disease (NAFLD), suggesting an inflammatory response by the activation of monocytes and macrophages and accelerating the disease progression. In the pathogenesis of NAFLD and liver fibrosis, the endogenous cannabinoids and their major receptors CB1 and CB2 appear to be highly involved. This study aimed at evaluating the expression of cannabinoids receptors (CB1R and CB2R) in plasma-derived exosomes extracted from patients with NAFLD, as well as investigating the in vitro effects of the circulating exosomes in cultured human HepaRG cells following their introduction into the culture medium. The results demonstrated that plasma-derived exosomes from NAFLD patients are vehicles for the transport of CB1R and are able to modulate CB receptors’ expression in HepaRG cells. In particular, circulating exosomes from NAFLD patients are inflammatory drivers for HepaRG cells, acting through CB1R activation and the downregulation of CB2R. Moreover, CB1R upregulation was associated with increased expression levels of PPAR-γ, a well-known mediator of liver tissue injury. In conclusion, this study provides evidence for CB1R transport by exosomes and suggests that the in vitro effects of circulating exosomes from NAFLD patients are mediated by the expression of cannabinoid receptors.

Background/Objectives: Immune checkpoint inhibitors (ICIs) are increasingly used in hepatocellular carcinoma (HCC), but their application around liver transplantation (LT) remains controversial because checkpoint blockade may enhance antitumor immunity while disrupting graft tolerance. We systematically reviewed the available evidence on ICI exposure before LT and ICI therapy after LT for recurrent HCC. Methods: A PRISMA-guided systematic review with qualitative synthesis was performed. PubMed/MEDLINE, Embase, and Web of Science were searched from inception to 15 March 2026. Studies including adult patients with HCC treated with PD-1-, PD-L1-, and/or CTLA-4-targeting ICIs before LT or after LT for recurrent HCC were eligible. Results: Fifty-one studies were included. In the pre-LT setting, 25 studies reported 576 transplanted patients. Acute allograft rejection occurred in approximately 22% and graft loss in 3.8%, and shorter washout intervals were consistently associated with higher rejection risk. In the post-LT setting, 26 studies reported 117 recipients treated with ICIs; at least 22 rejection episodes (18.8%) were described, usually within 2–4 weeks of treatment initiation, with limited and inconsistent antitumor benefit. Conclusions: Pre-LT ICI use appears feasible in selected patients when adequate washout is respected. Post-LT ICI therapy remains high risk and should be reserved for highly selected cases within a multidisciplinary framework.