Inflammatory response in traumatic brain and spinal cord injury: The role of XCL1-XCR1 axis and T cells.

BACKGROUND: Traumatic brain injury (TBI) and spinal cord injury (SCI) are acquired injuries to the central nervous system (CNS) caused by external forces that cause temporary or permanent sensory and motor impairments and the potential for long-term disability or even death. These conditions currently lack effective treatments and impose substantial physical, social, and economic burdens on millions of people and families worldwide. TBI and SCI involve intricate pathological mechanisms, and the inflammatory response contributes significantly to secondary injury in TBI and SCI. It plays a crucial role in prolonging the post-CNS trauma period and becomes a focal point for a potential therapeutic intervention. Previous research on the inflammatory response has traditionally concentrated on glial cells, such as astrocytes and microglia. However, increasing evidence highlights the crucial involvement of lymphocytes in the inflammatory response to CNS injury, particularly CD8+ T cells and NK cells, along with their downstream XCL1-XCR1 axis. OBJECTIVE: This review aims to provide an overview of the role of the XCL1-XCR1 axis and the T-cell response in inflammation caused by TBI and SCI and identify potential targets for therapy. METHODS: We conducted a comprehensive search of PubMed and Web of Science using relevant keywords related to the XCL1-XCR1 axis, T-cell response, TBI, and SCI. RESULTS: This study examines the upstream and downstream pathways involved in inflammation caused by TBI and SCI, including interleukin-15 (IL-15), interleukin-12 (IL-12), CD8+ T cells, CD4+ T cells, NK cells, XCL1, XCR1+ dendritic cells, interferon-gamma (IFN-γ), helper T0 cells (Th0 cells), helper T1 cells (Th1 cells), and helper T17 cells (Th17 cells). We describe their proinflammatory effect in TBI and SCI. CONCLUSIONS: The findings suggest that the XCL1-XCR1 axis and the T-cell response have great potential for preclinical investigations and treatments for TBI and SCI.

Lemierre's syndrome complicating multiple organ failure caused by Fusobacterium necrophorum subsp. funduliforme F1260: Case report and review.

We described a case of a 24-year-old man with multiple organ failure caused by Fusobacterium necrophorum subsp. funduliforme F1260. This is the first described case of Lemierre's syndrome with multiple organ failure due to F. necrophorum subsp. funduliforme F1260 in an adult in China. Our study highlights that there may be a risk of misdiagnosis based solely on typical manifestations of internal jugular vein thrombophlebitis, metastatic lesions, and F. necrophorum isolated from blood cultures or normally sterile sites. Clinicians should be cognizant of the potential utility of metagenomic next-generation sequencing in facilitating early pathogen detection in severe infections, thus enabling timely and appropriate administration of antibiotics to reduce mortality rates and improve prognosis.

Role of dendritic cells in spinal cord injury.

BACKGROUND: Inflammation can worsen spinal cord injury (SCI), with dendritic cells (DCs) playing a crucial role in the inflammatory response. They mediate T lymphocyte differentiation, activate microglia, and release cytokines like NT-3. Moreover, DCs can promote neural stem cell survival and guide them toward neuron differentiation, positively impacting SCI outcomes. OBJECTIVE: This review aims to summarize the role of DCs in SCI-related inflammation and identify potential therapeutic targets for treating SCI. METHODS: Literature in PubMed and Web of Science was reviewed using critical terms related to DCs and SCI. RESULTS: The study indicates that DCs can activate microglia and astrocytes, promote T-cell differentiation, increase neurotrophin release at the injury site, and subsequently reduce secondary brain injury and enhance functional recovery in the spinal cord. CONCLUSIONS: This review highlights the repair mechanisms of DCs and their potential therapeutic potential for SCI.

Melatonin exerts neuroprotective effects in mice with spinal cord injury by activating the Nrf2/Keap1 signaling pathway via the MT2 receptor.

Spinal cord injury (SCI) is a devastating event that often leads to severe disability, and effective treatments for SCI are currently limited. The present study investigated the potential effects and specific mechanisms of melatonin treatment in SCI. Mice were divided into Sham (Sham), Vehicle (Veh), Melatonin (Mel), and Melatonin + 4-phenyl-2-propionamidotetralin (4P-PDOT) (Mel + 4PP) groups based on randomized allocation. The expression of MT2 and the nuclear factor-erythroid 2-related factor 2 (Nrf2)/Keap1 signaling pathways were examined, along with oxidative stress indicators, inflammatory factors and GFAP-positive cells near the injury site. The polarization of microglial cells in different inflammatory microenvironments was also observed. Cell survival, motor function recovery and spinal cord tissue morphology were assessed using staining and Basso Mouse Scale scores. On day 7 after SCI, the results revealed that melatonin treatment increased MT2 protein expression and activated the Nrf2/Keap1 signaling pathway. It also reduced GFAP-positive cells, mitigated oxidative stress, and suppressed inflammatory responses around the injury site. Furthermore, melatonin treatment promoted the polarization of microglia toward the M2 type, increased the number of neutrophil-positive cells, and modulated the transcription of Bax and Bcl2 in the injured spinal cord. Melatonin treatment alleviated the severity of spinal injuries and facilitated functional recovery in mice with SCI. Notably, blocking MT2 with 4P-PDOT partially reversed the neuroprotective effects of melatonin in SCI, indicating that the activation of the MT2/Nrf2/Keap1 signaling pathway contributes to the neuroprotective properties of melatonin in SCI. The therapeutic and translational potentials of melatonin in SCI warrant further investigation.

Integrative analysis of TBI data reveals Lgmn as a key player in immune cell-mediated ferroptosis.

BACKGROUND: Traumatic brain injury (TBI) is a central nervous system disease caused by external trauma, which has complex pathological and physiological mechanisms. The aim of this study was to explore the correlation between immune cell infiltration and ferroptosis post-TBI. METHODS: This study utilized the GEO database to download TBI data and performed differentially expressed genes (DEGs) and ferroptosis-related differentially expressed genes (FRDEGs) analysis. DEGs were further analyzed for enrichment using the DAVID 6.8. Immunoinfiltration cell analysis was performed using the ssGSEA package and the Timer2.0 tool. The WGCNA analysis was then used to explore the gene modules in the data set associated with differential expression of immune cell infiltration and to identify the hub genes. The tidyverse package and corrplot package were used to calculate the correlations between hub genes and immune cell infiltration and ferroptosis-marker genes. The miRDB and TargetScan databases were used to predict complementary miRNAs for the Hub genes selected from the WGCNA analysis, and the DIANA-LncBasev3 tool was used to identify target lncRNAs for the miRNAs, constructing an mRNA-miRNA-lncRNA regulatory network. RESULTS: A total of 320 DEGs and 21 FRDEGs were identified in GSE128543. GO and KEGG analyses showed that the DEGs after TBI were primarily associated with inflammation and immune response. Xcell and ssGSEA immune infiltration cell analysis showed significant infiltration of T cell CD4+ central memory, T cell CD4+ Th2, B cell memory, B cell naive, monocyte, macrophage, and myeloid dendritic cell activated. The WGCNA analysis identified two modules associated with differentially expressed immune cells and identified Lgmn as a hub gene associated with immune infiltrating cells. Lgmn showed significant correlation with immune cells and ferroptosis-marker genes, including Gpx4, Hspb1, Nfe2l2, Ptgs2, Fth1, and Tfrc. Finally, an mRNA-miRNA-lncRNA regulatory network was constructed using Lgmn. CONCLUSION: Our results indicate that there is a certain correlation between ferroptosis and immune infiltrating cells in brain tissue after TBI, and that Lgmn plays an important role in this process.

Application of machine learning standardized integral area algorithm in measuring the scoliosis.

This study was to develop a computer vision evaluation method to automatically measure the degree of scoliosis based on the machine learning algorithm. For the X-ray images of 204 patients with idiopathic scoliosis who underwent full-spine radiography, histogram equalization of original image was performed before a flipping method was used to magnify asymmetric elements, search for the global maximum pixel value in each line, and scan local maximal pixel value, with the intersection set of two point sets being regarded as candidate anchor points. All fine anchors were fitted with cubic spline algorithm to obtain the approximate curve of the spine, and the degree of scoliosis was measured by the standardized integral area. All measured data were analyzed. In manual measurement, the Cobb angle was 11.70-25.00 (20.15 ± 3.60), 25.20-44.70 (33.89 ± 5.41), and 45.10-49.40 (46.98 ± 1.25) in the mild, moderate and severe scoliosis group, respectively, whereas the value for the standardized integral area algorithm was 0.072-0.298 (0.185 ± 0.040), 0.100-0.399 (0.245 ± 0.050), and 0.246-0.901 (0.349 ± 0.181) in the mild, moderate and severe scoliosis group, respectively. Correlation analysis between the manual measurement of the Cobb angle and the evaluation of the standardized integral area algorithm demonstrated the Spearman correlation coefficient r = 0.643 (P < 0.001). There was a positive correlation between the manual measurement of the Cobb angle and the measurement of the standardized integral area value. Two methods had good consistency in evaluating the degree of scoliosis. ROC curve analysis of the standardized integral area algorithm to measure the degree of scoliosis showed he cutoff value of the standardized integral area algorithm was 0.20 for the moderate scoliosis with an AUC of 0.865, sensitivity 0.907, specificity 0.635, accuracy 0.779, positive prediction value 0.737 and negative prediction value 0.859, and the cutoff value of the standardized integral area algorithm was 0.40 for the severe scoliosis with an AUC of 0.873, sensitivity 0.188, specificity 1.00, accuracy 0.936, positive prediction value 1 and a negative prediction value 0.935. Using the standardized integral area as an independent variable and the Cobb angle as a dependent variable, a linear regression equation was established as Cobb angle = 13.36 + 70.54 × Standardized area, the model has statistical significance. In conclusion, the integrated area algorithm method of machine learning can quickly and efficiently assess the degree of scoliosis and is suitable for screening the degree of scoliosis in a large dataset as a useful supplement to the fine measurement of scoliosis Cobb angle.

Structure and activation mechanism of the rice Salt Overly Sensitive 1 (SOS1) Na+/H+ antiporter.

Salinity is one of the most severe abiotic stresses that adversely affect plant growth and agricultural productivity. The plant Na+/H+ antiporter Salt Overly Sensitive 1 (SOS1) located in the plasma membrane extrudes excess Na+ out of cells in response to salt stress and confers salt tolerance. However, the molecular mechanism underlying SOS1 activation remains largely elusive. Here we elucidate two cryo-electron microscopy structures of rice (Oryza sativa) SOS1, a full-length protein in an auto-inhibited state and a truncated version in an active state. The SOS1 forms a dimeric architecture, with an NhaA-folded transmembrane domain portion in the membrane and an elongated cytosolic portion of multiple regulatory domains in the cytoplasm. The structural comparison shows that SOS1 adopts an elevator transport mechanism accompanied by a conformational transition of the highly conserved Pro148 in the unwound transmembrane helix 5 (TM5), switching from an occluded conformation in the auto-inhibited state to a conducting conformation in the active state. These findings allow us to propose an inhibition-release mechanism for SOS1 activation and elucidate how SOS1 controls Na+ homeostasis in response to salt stress.

Mpox multi-antigen mRNA vaccine candidates by a simplified manufacturing strategy afford efficient protection against lethal orthopoxvirus challenge.

Current unprecedented mpox outbreaks in non-endemic regions represent a global public health concern. Although two live-attenuated vaccinia virus (VACV)-based vaccines have been urgently approved for people at high risk for mpox, a safer and more effective vaccine that can be available for the general public is desperately needed. By utilizing a simplified manufacturing strategy of mixing DNA plasmids before transcription, we developed two multi-antigen mRNA vaccine candidates, which encode four (M1, A29, B6, A35, termed as Rmix4) or six (M1, H3, A29, E8, B6, A35, termed as Rmix6) mpox virus antigens. We demonstrated that those mpox multi-antigen mRNA vaccine candidates elicited similar potent cross-neutralizing immune responses against VACV, and compared to Rmix4, Rmix6 elicited significantly stronger cellular immune responses. Moreover, immunization with both vaccine candidates protected mice from the lethal VACV challenge. Investigation of B-cell receptor (BCR) repertoire elicited by mpox individual antigen demonstrated that the M1 antigen efficiently induced neutralizing antibody responses, and all neutralizing antibodies among the top 20 frequent antibodies appeared to target the same conformational epitope as 7D11, revealing potential vulnerability to viral immune evasion. Our findings suggest that Rmix4 and Rmix6 from a simplified manufacturing process are promising candidates to combat mpox.

Structure-based neutralizing mechanisms for SARS-CoV-2 antibodies.

The devastating economic and public health consequences caused by the COVID-19 pandemic have prompted outstanding efforts from the scientific community and pharmaceutical companies to develop antibody-based therapeutics against SARS-CoV-2. Those efforts are encouraging and fruitful. An unprecedentedly large number of monoclonal antibodies (mAbs) targeting a large spectrum of epitopes on the spike protein has been developed in the last two years. The development of structural biology, especially the cryo-EM technology, provides structural insights into the molecular neutralizing mechanisms of those mAbs. Moreover, neutralizing antibodies are essential in protecting host from infection. Therefore, understanding the antibody neutralizing mechanism is critical for optimizing effective antibody-based therapeutics and developing next-generation pan-coronavirus vaccines. This review summarizes the latest understanding of antibody neutralizing mechanisms against SARS-CoV-2 at the molecular and structural levels.

Probing Protein-DNA Conformational Dynamics in DNA Damage Recognition: Xeroderma Pigmentosum Group A Stabilizes the Damaged DNA-RPA14 Complex by Controlling Conformational Fluctuation Dynamics.

DNA damage inside biological systems may result in diseases like cancer. One of the major repairing mechanisms is the nucleotide excision repair (NER) that recognizes and repairs the damage caused by several internal and external exposures, such as DNA double-strand distortion due to the chemical modifications. Recognition of lesions is the initial stage of the DNA damage repair, which occurs with the help of several proteins like Replication Protein A (RPA) and Xeroderma Pigmentosum group A (XPA). The recognition process involves complex conformational dynamics of the proteins. Studying the dynamics of damage recognition by these proteins helps us to understand the mechanism and to develop therapeutics to increase the efficiency of recognition. Here, we use single-molecule fluorescence fluctuation measurements of a dye, labeled at a damaged position on DNA, to understand the interaction of the damage site with RPA14 and XPA. Our results suggest that interactive conformational dynamics of RPA14 with damaged DNA is inhomogeneous due to its low affinity for DNA, whereas binding of XPA with the already formed DNA-RPA14 complex may increase the specificity of damage recognition by controlling the conformational fluctuation dynamics of the complex.

A centric view of JAK/STAT5 in intestinal homeostasis, infection, and inflammation.

Cytokines, growth factors or hormones take action through the JAK/STAT5 signaling pathway, which plays a critical role in regulating the intestinal response to infection and inflammation. However, the way in which STAT5 regulates intestinal epithelial compartment is largely ignored due to the lack of genetic tools for proper exploration and because the two STAT5 transcription factors (STAT5A and STAT5B) have some redundant but also distinct functions. In this review article, by focusing on STAT5 functions in the intestinal undifferentiated and differentiated epithelia, we discuss major advances of the growth factor/cytokine-JAK/STAT5 research in view of intestinal mucosal inflammation and immunity. We highlight the gap in the research of the intestinal STAT5 signaling to anticipate the gastrointestinal explorative insights. Furthermore, we address the critical questions to illuminate how STAT5 signaling influences intestinal epithelial cell differentiation and stem cell regeneration during homeostasis and injury. Overall, our article provides a centric view of the relevance of the relationship between chronic inflammatory diseases and JAK/STAT5 pathway and it also gives an example of how chronic infection and inflammation pirate STAT5 signaling to worsen intestinal injuries. Importantly, our review suggests how to protect a wound healing from gastrointestinal diseases by modulating intestinal STAT5.

Structural basis for nucleosome-mediated inhibition of cGAS activity.

Activation of cyclic GMP-AMP synthase (cGAS) through sensing cytosolic double stranded DNA (dsDNA) plays a pivotal role in innate immunity against exogenous infection as well as cellular regulation under stress. Aberrant activation of cGAS induced by self-DNA is related to autoimmune diseases. cGAS accumulates at chromosomes during mitosis or spontaneously in the nucleus. Binding of cGAS to the nucleosome competitively attenuates the dsDNA-mediated cGAS activation, but the molecular mechanism of the attenuation is still poorly understood. Here, we report two cryo-electron microscopy structures of cGAS-nucleosome complexes. The structures reveal that cGAS interacts with the nucleosome as a monomer, forming 1:1 and 2:2 complexes, respectively. cGAS contacts the nucleosomal acidic patch formed by the H2A-H2B heterodimer through the dsDNA-binding site B in both complexes, and could interact with the DNA from the other symmetrically placed nucleosome via the dsDNA-binding site C in the 2:2 complex. The bound nucleosome inhibits the activation of cGAS through blocking the interaction of cGAS with ligand dsDNA and disrupting cGAS dimerization. R236A or R255A mutation of cGAS impairs the binding between cGAS and the nucleosome, and largely relieves the nucleosome-mediated inhibition of cGAS activity. Our study provides structural insights into the inhibition of cGAS activity by the nucleosome, and advances the understanding of the mechanism by which hosts avoid the autoimmune attack caused by cGAS.

Mechanistic Insights into the Hydrogen Oxidation Reaction on PtNi Alloys in Alkaline Media: A First-Principles Investigation.

The promising alkaline anion exchange membrane fuel cell suffers from sluggish kinetics of the hydrogen oxidation reaction (HOR). However, the puzzling HOR mechanism hinders the further development of highly active catalysts in alkaline media. In this work, we conducted detailed first-principles calculations to acquire a deep understanding of the alkaline HOR mechanism on PtNi bulk alloys [Pt3Ni(111), Pt2Ni2(111), and PtNi3(111)] and its surface alloy [PtNisurf(111)]. The full free energy profiles suggest that the HOR on PtNi alloys proceeds via the Tafel-Volmer mechanism, that is, the direct decomposition of H2 into two adsorbed H, followed by its reaction with OH- in the electrolyte, as the rate-determining step, to form H2O. Therefore, the HOR activity of PtNi alloys is solely impacted by the adsorption of hydrogen, rather than hydroxyl species, though the oxophilicity is also enhanced by alloying Pt with Ni. Thermodynamically, a moderate H adsorption free energy, ΔGH* ≈ 0.414 eV, is calculated to be an optimal candidate for the HOR at pH = 13. Alloying Pt with Ni can elevate the d-band center (εd), push the value of ΔGH* closer to 0.414 eV, and thus lower the free energy barrier (Ea) of the rate-determining Volmer reaction, leading to the highest HOR activity of PtNi3(111) among all considered PtNi alloys. This situation is further confirmed by both the microkinetic model and the Tafel plot, where PtNi3(111) exhibits the highest reaction rate (r = 9.42 × 103 s-1 site-1) and the largest exchange current density (i0 = 1.42 mA cm-2) for HOR in alkaline media. This work provides a fundamental understanding of the HOR mechanism and theoretical guidance for rational design of electrocatalysts for HOR in alkaline media.

Protein O-GlcNAc Modification Links Dietary and Gut Microbial Cues to the Differentiation of Enteroendocrine L Cells.

Intestinal L cells regulate a wide range of metabolic processes, and L-cell dysfunction has been implicated in the pathogenesis of obesity and diabetes. However, it is incompletely understood how luminal signals are integrated to control the development of L cells. Here we show that food availability and gut microbiota-produced short-chain fatty acids control the posttranslational modification on intracellular proteins by O-linked ß-N-acetylglucosamine (O-GlcNAc) in intestinal epithelial cells. Via FOXO1 O-GlcNAcylation, O-GlcNAc transferase (OGT) suppresses expression of the lineage-specifying transcription factor Neurogenin 3 and, thus, L cell differentiation from enteroendocrine progenitors. Intestinal epithelial ablation of OGT in mice not only causes L cell hyperplasia and increased secretion of glucagon-like peptide 1 (GLP-1) but also disrupts gut microbial compositions, which notably contributes to decreased weight gain and improved glycemic control. Our results identify intestinal epithelial O-GlcNAc signaling as a brake on L cell development and function in response to nutritional and microbial cues.

High-performance aqueous sodium-ion battery using a hybrid electrolyte with a wide electrochemical stability window.

The practical application of aqueous sodium-ion batteries (ASIBs) is limited by the electrolysis of water, which results in a low working voltage and energy density of ASIBs. Here, a NaClO4-based acetonitrile/water hybrid electrolyte (NaClO4(H2O)2AN2.4) is applied to ASIBs for the first time, which effectively extends the electrochemical stability window (ESW) to 3.0 V and reduces the internal resistance of the battery. Based on this hybrid electrolyte, an ASIB full cell using carbon coated Na2.85K0.15V2(PO4)3 and NaTi2(PO4)3 as the cathode and anode materials, respectively, can afford a discharge capacity and energy density of 52 mA h g-1 and 51 W h kg-1, respectively, at a current density of 1 A g-1. The energy density of this battery exceeds almost all reported traditional ASIBs.

Lgr5+ intestinal stem cell sorting and organoid culture.

Intestinal epithelial stem cells (IESCs) are one of the most rapidly self-renewing and proliferating adult stem cells. The IESCs reside at the bottom of intestinal and colonic crypts, giving rise to all intestinal epithelial lineages and maintaining intestinal epithelial replenishment. The technique of three-dimensional culture based upon intestinal stem cell biology has been recently developed to study gastrointestinal development and disease pathogenesis. Here, we summarize the techniques used to isolate Lgr5-positive IESCs to form the enteroids from intestine or colonoids from colon, and present the means to examine these organoid functions. This study will provide a simple and practical way for producing intestinal tissues in the laboratory.

Constitutive STAT5 activation regulates Paneth and Paneth-like cells to control Clostridium difficile colitis.

Clostridium difficile impairs Paneth cells, driving intestinal inflammation that exaggerates colitis. Besides secreting bactericidal products to restrain C. difficile, Paneth cells act as guardians that constitute a niche for intestinal epithelial stem cell (IESC) regeneration. However, how IESCs are sustained to specify Paneth-like cells as their niche remains unclear. Cytokine-JAK-STATs are required for IESC regeneration. We investigated how constitutive STAT5 activation (Ca-pYSTAT5) restricts IESC differentiation towards niche cells to restrain C. difficile infection. We generated inducible transgenic mice and organoids to determine the effects of Ca-pYSTAT5-induced IESC lineages on C. difficile colitis. We found that STAT5 absence reduced Paneth cells and predisposed mice to C. difficile ileocolitis. In contrast, Ca-pYSTAT5 enhanced Paneth cell lineage tracing and restricted Lgr5 IESC differentiation towards pYSTAT5+Lgr5-CD24+Lyso+ or cKit+ niche cells, which imprinted Lgr5hiKi67+ IESCs. Mechanistically, pYSTAT5 activated Wnt/ß-catenin signaling to determine Paneth cell fate. In conclusion, Ca-pYSTAT5 gradients control niche differentiation. Lack of pYSTAT5 reduces the niche cells to sustain IESC regeneration and induces C. difficile ileocolitis. STAT5 may be a transcription factor that regulates Paneth cells to maintain niche regeneration.

Cell Metabolism Control Through O-GlcNAcylation of STAT5: A Full or Empty Fuel Tank Makes a Big Difference for Cancer Cell Growth and Survival.

O-GlcNAcylation is a post-translational modification that influences tyrosine phosphorylation in healthy and malignant cells. O-GlcNAc is a product of the hexosamine biosynthetic pathway, a side pathway of glucose metabolism. It is essential for cell survival and proper gene regulation, mirroring the metabolic status of a cell. STAT3 and STAT5 proteins are essential transcription factors that can act in a mutational context-dependent manner as oncogenes or tumor suppressors. They regulate gene expression for vital processes such as cell differentiation, survival, or growth, and are also critically involved in metabolic control. The role of STAT3/5 proteins in metabolic processes is partly independent of their transcriptional regulatory role, but is still poorly understood. Interestingly, STAT3 and STAT5 are modified by O-GlcNAc in response to the metabolic status of the cell. Here, we discuss and summarize evidence of O-GlcNAcylation-regulating STAT function, focusing in particular on hyperactive STAT5A transplant studies in the hematopoietic system. We emphasize that a single O-GlcNAc modification is essential to promote development of neoplastic cell growth through enhancing STAT5A tyrosine phosphorylation. Inhibition of O-GlcNAcylation of STAT5A on threonine 92 lowers tyrosine phosphorylation of oncogenic STAT5A and ablates malignant transformation. We conclude on strategies for new therapeutic options to block O-GlcNAcylation in combination with tyrosine kinase inhibitors to target neoplastic cancer cell growth and survival.

Hepatic growth hormone - JAK2 - STAT5 signalling: Metabolic function, non-alcoholic fatty liver disease and hepatocellular carcinoma progression.

The rising prevalence of obesity came along with an increase in associated metabolic disorders in Western countries. Non-alcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of the metabolic syndrome and is linked to primary stages of liver cancer development. Growth hormone (GH) regulates various vital processes such as energy supply and cellular regeneration. In addition, GH regulates various aspects of liver physiology through activating the Janus kinase (JAK) 2- signal transducer and activator of transcription (STAT) 5 pathway. Consequently, disrupted GH - JAK2 - STAT5 signaling in the liver alters hepatic lipid metabolism and is associated with NAFLD development in humans and mouse models. Interestingly, while STAT5 as well as JAK2 deficiency correlates with hepatic lipid accumulation, recent studies suggest that these proteins have unique ambivalent functions in chronic liver disease progression and tumorigenesis. In this review, we focus on the consequences of altered GH - JAK2 - STAT5 signaling for hepatic lipid metabolism and liver cancer development with an emphasis on lessons learned from genetic knockout models.