Activation of thyroid hormone receptor β (THRβ) has shown beneficial effects on metabolic alterations, including non-alcoholic fatty liver disease (NAFLD). Here, we investigated the effect of TG68, a novel THRβ agonist, on fatty liver accumulation and liver injury in mice fed a high-fat diet (HFD). C57BL/6 mice fed HFD for 17 or 18 weeks, a time when all mice developed massive steatohepatitis, were then given TG68 at a dose of 9.35 or 2.8 mg/kg for 2 or 3 weeks, respectively. As a reference compound, the same treatment was adopted using equimolar doses of MGL-3196, a selective THRβ agonist currently in clinical phase III. The results showed that treatment with TG68 led to a reduction in liver weight, hepatic steatosis, serum transaminases, and circulating triglycerides. qRT-PCR analyses demonstrated activation of THRβ, as confirmed by increased mRNA levels of Deiodinase-1 and Malic enzyme-1, and changes in lipid metabolism, as revealed by increased expression of Acyl-CoA Oxidase-1 and Carnitine palmitoyltransferase-1. The present results showed that this novel THRβ agonist exerts an anti-steatogenic effect coupled with amelioration of liver injury in the absence of extra-hepatic side effects, suggesting that TG68 may represent a useful tool for the treatment of NAFLD.

Steatotic liver disease (SLD) refers to a spectrum of diseases caused by hepatic lipid accumulation. SLD has emerged as the leading cause of chronic liver disease worldwide. Despite this burden and many years, understanding the pathophysiology of this disease is challenging due to the inaccessibility to human liver specimens. Therefore, cell-based in vitro systems are widely used as models to investigate the pathophysiology of SLD. Culturing hepatic cells in monolayers causes the loss of their hepatocyte-specific phenotype and, consequently, tissue-specific function and architecture. Hence, three-dimensional (3D) culture models allow cells to mimic the in vivo microenvironment and spatial organization of the liver unit. The utilization of 3D in vitro models minimizes the drawbacks of two-dimensional (2D) cultures and aligns with the 3Rs principles to alleviate the number of in vivo experiments. This article provides an overview of liver 3D models highlighting advantages and limitations, and culminates by discussing their applications in pharmaceutical and biomedical research.

MBOAT7 is a protein anchored to endomembranes by several transmembrane domains. It has a catalytic dyad involved in remodelling of phosphatidylinositol with polyunsaturated fatty acids. Genetic variants in the MBOAT7 gene have been associated with the entire spectrum of non‐alcoholic fatty liver (NAFLD), recently redefined as metabolic dysfunction‐associated fatty liver disease (MAFLD) and, lately, steatotic liver disease (SLD), and to an increasing number of extrahepatic conditions. In this review, we will (a) elucidate the molecular mechanisms by which MBOAT7 loss‐of‐function predisposes to MAFLD and neurodevelopmental disorders and (b) discuss the growing number of genetic studies linking MBOAT7 to hepatic and extrahepatic diseases. MBOAT7 complete loss of function causes severe changes in brain development resulting in several neurological manifestations. Lower MBOAT7 hepatic expression at both the mRNA and protein levels, due to missense nucleotide polymorphisms (SNPs) in the locus containing the MBOAT7 gene, affects specifically metabolic and viral diseases in the liver from simple steatosis to hepatocellular carcinoma, and potentially COVID‐19 disease. This body of evidence shows that phosphatidylinositol remodelling is a key factor for human health.

Plastic compounds released into the environment can be accumulated in human tissues causing various health issues. It has been demonstrated that Bisphenol A (BPA), widely used in polycarbonate plastics and food packaging, can accumulate in gastrointestinal (GI) tract, inducing oxidative stress, metabolic dysfunction, and other cellular disturbances, including mitochondrial damage. However, the mechanisms by which BPA affects the GI function and affects mitochondrial function in the absorptive cells of the intestine, are still not completely understood. The aim of this study is to investigate whether BPA enters intact human intestinal cells and affects mitochondrial electron transport chain (ETC) function. High-resolution respirometry (O2k system, OROBOROS) and fluorometry were used to assess mitochondrial respiration and membrane potential (mt-MP) in Caco-2 cells under acute exposure to BPA. Cellular respiration was stimulated with complex I (C-I), II (C-II), IV (C-IV) and β-oxidation substrates in both intact and permeabilized Caco-2 cells. Morphological analysis of cells exposed to BPA was performed by electron microscopy. In intact cells, respiration rate decreased in presence of BPA, thus confirming the detrimental effects of BPA on ETC. In permeabilized cells, BPA caused a decrease of respiratory activity in presence of C-I and C-II substrates following a reduction of the ETC oxidative capacity and a depolarization of mt-MP. Morphological analysis suggested that BPA can be internalized by endocytosis. The reduced respiration rate in both intact and permeabilized cells indicates that BPA reaches mitochondria even without membrane permeabilization. BPA compromises both oxidative phosphorylation (OxPhos) and mt-MP, thus leading to an impairment of energy metabolism that could contribute to pathological alterations of the gastrointestinal function.

Liver regeneration is increasingly recognized as a process influenced not only by hepatocellular signaling but also by the gut–liver axis, where gut microbiota‐derived metabolites, immune mediators, and extracellular vesicles modulate hepatic recovery after liver damage. In this review, we explore recent progress in understanding the gut microbiota's role in liver regeneration and discuss its therapeutic potential in the context of hepatic surgery and liver transplantation. Emerging evidence shows that beneficial microbial taxa, including Akkermansia muciniphila , Bifidobacterium longum , and Parabacteroides distasonis , enhance liver regeneration by regulating short‐chain fatty acid production, bile acid metabolism, and tricarboxylic acid cycle pathways, while dysbiosis and microbial translocation can impair regenerative outcomes. Key host‐microbiome interactions, particularly the Farnesoid X Receptor (FXR)‐Fibroblast Growth Factor 19 (FGF19) signaling axis, play a central role in protecting hepatocytes from bile acid overload and supporting regeneration, highlighting the therapeutic potential of FXR agonists, FGF19 mimetics, probiotics, dietary interventions, and metabolite supplementation. At the same time, monitoring bile acids profiles alongside gut microbiota composition may allow early detection and prevention of complications. In addition, microbial‐derived markers such as the lipopolysaccharide/lipoteichoic acid ratio may serve as predictive biomarkers for post‐hepatectomy liver failure. Adjunctive approaches, including vitamin D supplementation, may further support regeneration through vitamin D receptor‐mediated regulation of bile acid homeostasis and cell‐cycle progression. In the context of live donor liver transplantation, the detection of occult bacteremia further underscores the complexity of host‐microbiome interactions and suggests that microbiological surveillance could improve postoperative management. Collectively, these findings emphasize the importance of microbiota‐targeted strategies to improve hepatic regeneration, reduce postoperative complications, and optimize outcomes following liver surgery and transplantation.