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In this issue of Nature Metabolism, Wang et al. identified a non-apoptotic caspase-8 function in metabolic dysfunction-associated steatohepatitis (MASH), in which hepatocyte-derived caspase-8 induces meteorin, which in turn activates hepatic stellate cells (HSCs) to drive fibrosis. This function reveals a potential therapeutic target to directly address fibrosis and reduce the progression of metabolic dysfunction-associated steatotic liver disease (MASLD).

De Palma and colleagues develop a dendritic cell therapy based on dendritic cell progenitors engineered to produce IL-12 and FLT3L and show antigen-agnostic reduction of tumor burden that can be exploited for combination therapy in glioma.

The transcription factor ATF6 causes an enrichment in long-chain fatty acids in the colonic epithelium, which leads to changes in the gut microbiota and contributes to the development of colorectal cancer in humans and mice, thereby linking endoplasmic reticulum stress responses to lipid metabolism and tumorigenesis.

Interact-omics, a high-throughput cytometry-based framework, resolves the cellular interaction landscape.

Non-antibiotic drugs from a wide range of therapeutic classes can alter the ability of gut commensals to resist invasion by enteropathogens, a previously underappreciated side effect of such drugs.

In recent years, significant progress has been made in our understanding of the biology of prions, yet many fundamental questions remain unanswered. Aguzzi and Heikenwalder discuss some of these unanswered questions, focusing on the role of the immune system in prion pathogenesis.

There's a lot of disagreement among prion scientists, as a recent conference made very clear. Even the revered 'prion hypothesis' came under attack.

Myeloid-derived suppressor cells (MDSCs) residing within tumors can impede immune responses. Knolle and colleagues show that MDSCs poison immune cells by producing methylglyoxal, which functionally alters their cellular metabolism and hence their effector responses.

Inhibition of S6 kinase 1 (S6K1) extends lifespan in mice, but the underlying mechanisms are not fully understood. Here Gallage et al. show that reduction of S6K signaling diminishes inflammation in the aged mouse liver via suppression of the senescence-associated secretory phenotype.

Roland Rad and colleagues report development of a new conditional piggyBac transposition system for performing insertional mutagenesis screens in mice. They apply the system to identify new oncogenic driver pathways for pancreatic cancer.

Single-cell analyses reveal cDC1 as conserved immunological drivers of non-alcoholic steatohepatitis in mice and humans

SpaceM combines light microscopy and MALDI-imaging mass spectrometry to enable single-cell metabolic profiling of cultured cells. SpaceM reveals coexisting metabolic states of hepatocytes and aims to democratize single-cell metabolomics.

Blockade of lymphotoxin β-receptor (LTβR) signalling restores WNT signalling and epithelial repair in a model of chronic obstructive pulmonary disease.

Although it is now accepted that the infectious agent that causes transmissible spongiform encephalopathies is PrP^Sc, recent insights into the existence of prion strains pose a fascinating challenge to prion research. What is the nature of prion strains? And how can they be discriminated?

Identifying senescence is complicated by a lack of universal markers. Here, Duran et al. use nuclear morphology features to devise machine-learning classifiers that detect senescence in cell lines and liver sections of patients and mouse models of aging and disease.

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

The involvement of cell death pathways in the early stage of pancreatic ductal adenocarcinoma (PDAC) development, especially KRAS-dependent acinar-to-ductal metaplasia (ADM), remains to be investigated. Here, the authors find that TAK1 mediates cell survival during ADM transdifferentiation through suppression of apoptosis and necroptosis, which could be targeted for prevention and treatment of PDAC.

This study identifies candidate safeguard repressor transcription factors that repress alternate lineages in mature cell types and provides functional evidence that Prox1 performs such a function in hepatocytes during reprogramming, regeneration and in cancer.

Here, using human liver chimeric mice, the authors describe perturbation of the diurnal transcriptome and epigenome of human hepatocytes during hepatitis C virus infection, affecting pathways mediating metabolic alterations, fibrosis, and cancer, and further show that the pathways remain affected in patients with advanced liver disease.

Identification of cancer genes altered by non-genetic mechanisms in B-cell lymphoma is challenging. Here, the authors report the development of transposon tools to perform genome-wide recessive screens in vivo and validate identified putative tumor suppressor genes using a CRISPR/Cas9 validation platform.

CRISPR/Cas9 technology has been used for genome engineering in vivo. Here, the authors use a transfection technique to deliver multiple guide RNAs to the pancreas of adult mice, allowing genetic screening and chromosome engineering in pancreatic cancer.

Glucagon is hormone that signals via a dedicated g-protein coupled receptor, but downstream signaling is poorly understood. Here, Wu et al. uncover liver glucagon signaling using phosphoproteomics and define a role for the vesicle trafficking protein SEC22B in distinct metabolic actions.

Chronic infections are commonly established in the liver. Knolle and colleagues show that cytotoxic T lymphocyte responses can be boosted by TLR-mediated induction of myeloid aggregates (iMATES).

Primary liver cancer, of which hepatocellular carcinoma is the most common form, is the second leading cause of cancer-related death. Heikenwalder and colleagues review the important inflammatory component underlying hepatocellular carcinoma and consider potential directions for therapy.

Wang et al. show that the RNA methyltransferase Mettl3 contributes to hepatic sphingolipid homeostasis by promoting RNA decay of the sphingomyelinase Smpd3 during postnatal liver development, with Mettl3 deficiency leading to ceramide accumulation and liver developmental defects.

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.

Drug and target discovery for advanced liver disease are hampered by a lack of suitable models for clinical translation. Here the authors present a human liver cell-based system modeling a clinical prognostic signature allowing to propose nizatidine for treatment of advanced liver fibrosis and hepatocellular carcinoma prevention.

Cancer cells frequently harbour genetic aberrations that protect them from programmed cell death. Here, the authors show in non-small cell lung cancer that the anti-apoptotic gene MCL-1 is subject to copy number gains and that deletion of MCL-1 reduces tumour formation.

Zheng et al. show that ChAT-expressing cholinergic T cells suppress the development of liver cancer via their cholinergic activity, which constrains calcium/NFAT signaling induced by TCR engagement.

Idiopathic pulmonary fibrosis (IPF) is a lethal disease with insufficient treatment strategies. Here the authors show that reduction of the microRNA MIRLET7D and hyperactivation of EP300 contribute to impaired epigenetic silencing by the MiCEE complex in pulmonary fibroblasts of IPF patients, and demonstrate the benefit of inhibiting EP300 for the treatment of IPF.

Cachexia manifests in cancer, chronic inflammation and infections. Bergthaler and colleagues show that CD8⁺ T cells mediate infection-associated cachexia in a manner dependent on T cell–intrinsic type I IFN signaling and antigen recognition.

Dietary protein dilution, where protein is reduced and replaced by other nutrient sources without caloric restriction, promotes metabolic health via the hepatokine Fgf21. Here, the authors show that essential amino acids threonine and tryptophan are necessary and sufficient to induce these effects.

The tumour microenvironment determines which type of liver cancer develops, with transformed hepatocytes giving rise to intrahepatic cholangiocarcinoma or hepatocellular carcinoma depending or whether they are surrounded by cells undergoing necroptosis or apoptosis.

Haematopoietic stem cells (HSCs) are characterized by their self-renewal potential and associated dormancy. Here the authors show that niche produced netrin-1 preserves HSC quiescence and self-renewal via neogenin-1, and that decline of netrin-1 production during ageing leads to decreased Neo1 mediated HSC self-renewal.

Liver resident CD8 T cells have an essential role in immunopathology in a mouse model of nonalcoholic steatohepatitis, by becoming auto-aggressive following sequential transcriptional and metabolic activation steps .

Elevated hepatic alanine catabolism is shown to promote hyperglycaemia and reduce skeletal muscle protein synthesis, thereby linking sarcopenia with hyperglycaemia in the context of type 2 diabetes.

A mouse model of systemic versus mucosal exposure to microbial taxa reveals that the former provokes a flexible B cell response with a diverse immunoglobulin repertoire, whereas the latter generates a more-restricted response.