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Blockade of intrahepatic accumulation and function of platelets represents a potential approach to treat non-alcoholic steatohepatitis (NASH) and prevent subsequent progression to hepatocellular carcinoma

In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy.

Ectopic lipid accumulation and inflammation are the essential signs of NASH. Here, the authors show that hepatic WTAP is a key integrative repressor of ectopic lipid accumulation and inflammation during NASH progression, and hepatic deletion of Wtap promotes both of them, leading to NASH

Currently, there is no approved treatment for NAFLD and NASH. Here, Boland et al. show that the GLP-1R and GCGR dual-agonist cotadutide reduces hepatic steatosis, inflammation and fibrosis via GCGR agonism, and glucose homeostasis and weight gain by activating GLP-1 signalling.

Nicotine accumulates in the intestine during tobacco smoking and accelerates the progression of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis (NASH), but it can be degraded effectively by the human symbiont Bacteroides xylanisolvens.

Non-alcoholic steatohepatitis has with few well-defined biomarkers or clinically effective treatments but is promoted by inflammation. Here, the authors find an active lipid [So(d18:1)] that is significantly changed in patients and promotes inflammation by directly inhibiting macrophage HIF-2α.

Metabolic dysfunction-associated steatohepatitis (MASH) has an incompletely understood mechanistic basis. Here the authors use gain- and loss-of-function mouse models to show that that E3 ligase TRIM7 in hepatocyte promotes MASH pathogenesis via DUSP10 ubiquitination.

In this study Guo et al. show that skeletal muscle IRF4-FSTL1 exerts metabolic regulation on the liver via DIP2A/CD14 in NASH. FSTL1 from skeletal muscle that enters the circulation promotes the development of NASH.

Oxidative stress is closely linked with nonalcoholic steatohepatitis (NASH). Here, the authors show that palmitic acid stimulates NASH by inhibiting PRDX1 to increase oxidative stress, while rosmarinic acid improves NASH by activating PRDX1 to reduce oxidative stress.

Nonalcoholic steatohepatitis (NASH) is a heterogeneous disease with complicated pathogenesis. Here the authors identify that the E3 ligase TRIM26 confers protection against NASH development via suppression of CCAAT/enhancer binding protein delta (C/EBPδ).

Nonalcoholic steatohepatitis (NASH) is a devastating type of liver disease that is caused by hepatocellular death which triggers liver inflammation and fibrosis. Here, the authors show that MAP kinase phosphatase-1 promotes hepatocellular death thus, driving the development of NASH.

Hepatic bone morphogenetic protein 8b expression is shown to be induced in NASH to drive wound healing responses and NASH progression by promoting inflammatory pathways in hepatic stellate cells and, more broadly, in the liver parenchyma.

Although nonalcoholic fatty liver disease is the most prevalent liver disease worldwide, there is a paucity of good-quality data on its natural history and most studies to date have reported on retrospective data. Robust data are required to inform regulatory end points, trial design and models of care.

The high abundance of immunosuppressive, tumor-associated macrophages limits the efficacy of treatments against hepatocellular carcinoma. Here, the authors develop a nanoplatform for the co-delivery of FSP1 inhibitor and sorafenib that simultaneously targets tumor cells and M2-like macrophages, inducing ferroptosis and boosting anti-tumor immune responses in preclinical mouse models.

Impaired mitochondrial function in liver tissue may contribute to the pathogenesis and disease progression of nonalcoholic fatty liver disease (NAFLD). Here the authors report that patients with obesity have lower mitochondrial capacity in adipose tissues but higher capacity in the liver, without overall associations to NAFLD severity, and that bariatric surgery increases hepatic mitochondrial respiration and mitochondrial biogenesis.

The deubiquitinase CYLD regulates a TAK1–JNK pathway and can be targeted to ameliorate nonalcoholic steatohepatitis.

The receptor-interacting protein (RIPK1) promotes cell death and contributes to nonalcoholic steatohepatitis pathogenesis. Here the authors report that a SUMO-specific protease, SENP1, deSUMOylates RIPK1 and inhibits cell death in a mouse model of non-alcoholic fatty liver disease.

In the phase 3 MAESTRO-NAFLD-1 trial, the liver-targeted thyroid hormone receptor-β selective agonist resmetirom was well tolerated and improved liver biomarkers in adults with nonalcoholic fatty liver disease.

In this Review, Llovet and colleagues discuss advances in our knowledge of the pathogenesis and clinical management of nonalcoholic steatohepatitis-related hepatocellular carcinoma. They also discuss future prospects and unmet needs.

NAFLD is growing in prevalence worldwide, and has emerged as a leading cause of end-stage liver disease in many countries. In this Review, the authors describe the global epidemiology of NAFLD, discuss associated risk factors and outline challenges for screening and management.

The FLIGHT-FXR trial, testing farnesoid X receptor agonist tropifexor in nonalcoholic steatohepatitis, demonstrated sustained decreases in alanine aminotransferase levels and hepatic fat fraction, but not aspartate aminotransferase, with dose-dependent pruritus being the most common adverse event.

The mediobasal hypothalamus plays a central role in integrating nutritional and sex-related signals to regulate energy homeostasis. Here, through snRNA-seq of the mediobasal hypothalamus in female and male mice across nutritional states, authors show that Agrp neurons are nutrition-sensitive, DA neurons exhibit transcriptional differences in a sex-dependent manner, and KNDy neurons are responsive to both sex and nutrition.

Employing a candidate gene approach, Mancina et al. identify a genetic variant of the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene that reduces susceptibility to fatty liver disease. Functional studies in vitro and in vivo demonstrate that targeting PSD3 protects against fatty liver disease.

Structural changes mediated by advanced glycation end-products enhance extracellular matrix viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.

Spermidine, a polyamine reported to extend lifespan and reduce the risk of age-related diseases, serves as a substrate for the post-translational modification hypusination. Here the authors report that EIF5A hypusination, which regulates mitochondrial protein synthesis, is reduced during non-alcoholic steatohepatitis (NASH), which can be prevented by spermidine to inhibit the progression of NASH in mice.

A small-molecule aldolase inhibitor, aldolazin is reported and shown to selectively activate the lysosomal pool of AMPK, which has glucose-lowering effects in rodents.

Autophagosome-lysosome fusion is crucial to mitigate nonalcoholic fatty liver disease (NAFLD). Here, the authors demonstrate that CHIP mediates non-degradative ubiquitination of STX17, which enhances SNRAE complex formation, which alleviates NAFLD.

Nonalcoholic steatohepatitis (NASH) starts with lipid droplet accumulation in the liver that eventually causes inflammation and fibrosis. Here, authors use lipophagy activators to limit the accumulation of lipids in the liver and show that this can prevent disease progression in a mouse model of nonalcoholic steatohepatitis.

Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic.

Synthetic methylotrophic S. cerevisiae often faces energetic constrains during one-carbon assimilation. Here, the authors address this issue by engineering of heterologous methanol-formate-formaldehyde oxidation pathways to enable CO₂ assimilation via non-native Calvin cycle during methanol fermentation.

The mechanisms by which noncoding genetic variation shapes tissue macrophage phenotypic diversity remain obscure. Glass and colleagues define cell-intrinsic and environmental effects contributing to genetic control of Kupffer cell transcription.

A new study examines microbiome-generated ethanol in individuals with and without nonalcoholic fatty liver disease (NAFLD), concluding that microbial ethanol might contribute to pathogenesis in some patients with NAFLD.

A truncating variant of 17β-hydroxysteroid dehydrogenase-13 (17β-HSD13), a lipid droplet -associated protein, associates with lower risk of chronic liver disease. Here the authors identify a phosphorylation site in 17β-HSD13 which promotes lipolysis, and report that a knock-in mouse with a 17β-HSD13 mutant defective for phosphorylation is more susceptible to nonalcoholic steatohepatitis.

Obesity increases the risk of hepatocellular carcinoma (HCC) especially in men. Here the authors find a potential mechanistic explanation by showing that, in mice, obesity-induced STAT3 cooperates with the androgen receptor to activate the mTORC pathway through up regulation of CCRK, resulting in hepatic steatosis worsening and HCC development via metabolic and immune reprogramming.

In a phase 2b study, inhibition of hepatic stearoyl-CoA desaturase in patients with nonalcoholic steatohepatitis was safe and tolerated; although reductions in liver fat were not significant, changes in liver enzymes and histology were observed.

Understanding transcriptional responses to chemical perturbations is crucial for drug discovery. Here, authors present PRnet, a deep generative model that predicts gene responses to novel chemical perturbations, enabling in-silico drug screening and the identification of candidate compounds for various diseases.

Alterations in hepatic lipid metabolism may contribute to the onset of non-alcoholic fatty liver disease as well as other metabolic disorders. In this work, Zhou et al. identify orosomucoid 2 (ORM2) as a regulator of lipid homeostasis in the liver.