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Ferroptosis is a nonapoptotic form of programmed cell death that contributes to different neurological inflammatory diseases. However, whether HSV-1 induces ferroptosis in the CNS and the role of ferroptosis in viral pathogenesis remain unclear. Herpes simplex virus 1 (HSV-1) is a DNA virus belonging to the family Herpesviridae . HSV-1 infection causes severe neurological disease in the central nervous system (CNS), including encephalitis. Ferroptosis is a nonapoptotic form of programmed cell death that contributes to different neurological inflammatory diseases. However, whether HSV-1 induces ferroptosis in the CNS and the role of ferroptosis in viral pathogenesis remain unclear. Here, we demonstrate that HSV-1 induces ferroptosis, as hallmarks of ferroptosis, including Fe 2+ overload, reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, lipid peroxidation, and mitochondrion shrinkage, are observed in HSV-1-infected cultured human astrocytes, microglia cells, and murine brains. Moreover, HSV-1 infection enhances the E3 ubiquitin ligase Keap1 (Kelch-like ECH-related protein 1)-mediated ubiquitination and degradation of nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates the expression of antioxidative genes, thereby disturbing cellular redox homeostasis and promoting ferroptosis. Furthermore, HSV-1-induced ferroptosis is tightly associated with the process of viral encephalitis in a mouse model, and the ferroptosis-activated upregulation of prostaglandin-endoperoxide synthase 2 (PTGS2) and prostaglandin E 2 (PGE 2 ) plays an important role in HSV-1-caused inflammation and encephalitis. Importantly, the inhibition of ferroptosis by a ferroptosis inhibitor or a proteasome inhibitor to suppress Nrf2 degradation effectively alleviated HSV-1 encephalitis. Together, our findings demonstrate the interaction between HSV-1 infection and ferroptosis and provide novel insights into the pathogenesis of HSV-1 encephalitis. IMPORTANCE Ferroptosis is a nonapoptotic form of programmed cell death that contributes to different neurological inflammatory diseases. However, whether HSV-1 induces ferroptosis in the CNS and the role of ferroptosis in viral pathogenesis remain unclear. In the current study, we demonstrate that HSV-1 infection induces ferroptosis, as Fe 2+ overload, ROS accumulation, GSH depletion, lipid peroxidation, and mitochondrion shrinkage, all of which are hallmarks of ferroptosis, are observed in human cultured astrocytes, microglia cells, and murine brains infected with HSV-1. Moreover, HSV-1 infection enhances Keap1-dependent Nrf2 ubiquitination and degradation, which results in substantial reductions in the expression levels of antiferroptotic genes downstream of Nrf2, thereby disturbing cellular redox homeostasis and promoting ferroptosis. Furthermore, HSV-1-induced ferroptosis is tightly associated with the process of viral encephalitis in a mouse model, and the ferroptosis-activated upregulation of PTGS2 and PGE 2 plays an important role in HSV-1-caused inflammation and encephalitis. Importantly, the inhibition of ferroptosis by either a ferroptosis inhibitor or a proteasome inhibitor to suppress HSV-1-induced Nrf2 degradation effectively alleviates HSV-1-caused neuro-damage and inflammation in infected mice. Overall, our findings uncover the interaction between HSV-1 infection and ferroptosis, shed novel light on the physiological impacts of ferroptosis on the pathogenesis of HSV-1 infection and encephalitis, and provide a promising therapeutic strategy to treat this important infectious disease with a worldwide distribution.

Metastasis accounts for 90% of cancer-related deaths and, currently, there are no effective clinical therapies to block the metastatic cascade. A need to develop novel therapies specifically targeting fundamental metastasis processes remains urgent. Here, we demonstrate that Salmonella YB1, an engineered oxygen-sensitive strain, potently inhibits metastasis of a broad range of cancers. This process requires both IFN-γ and NK cells, as the absence of IFN-γ greatly reduces, whilst depletion of NK cells in vivo completely abolishes, the anti-metastatic ability of Salmonella . Mechanistically, we find that IFN-γ is mainly produced by NK cells during early Salmonella infection, and in turn, IFN-γ promotes the accumulation, activation, and cytotoxicity of NK cells, which kill the metastatic cancer cells thus achieving an anti-metastatic effect. Our findings highlight the significance of a self-regulatory feedback loop of NK cells in inhibiting metastasis, pointing a possible approach to develop anti-metastatic therapies by harnessing the power of NK cells. Cancer metastasis is one of the major causes of cancer related deaths and there is an urgent need to find more clinically effective metastasis targeting agents. Here, the authors show that Salmonella YB1 inhibits metastasis in multiple mouse models of cancer through a mechanism dependent on IFN-γ and NK cells.

One of the biggest hurdles for the development of metabolism-targeted therapies is to identify the responsive tumor subsets. However, the metabolic vulnerabilities for most human cancers remain unclear. Establishing the link between metabolic signatures and the oncogenic alterations of receptor tyrosine kinases (RTK), the most well-defined cancer genotypes, may precisely direct metabolic intervention to a broad patient population. By integrating metabolomics and transcriptomics, we herein show that oncogenic RTK activation causes distinct metabolic preference. Specifically, EGFR activation branches glycolysis to the serine synthesis for nucleotide biosynthesis and redox homeostasis, whereas FGFR activation recycles lactate to fuel oxidative phosphorylation for energy generation. Genetic alterations of EGFR and FGFR stratify the responsive tumors to pharmacological inhibitors that target serine synthesis and lactate fluxes, respectively. Together, this study provides the molecular link between cancer genotypes and metabolic dependency, providing basis for patient stratification in metabolism-targeted therapies. Cancer subtypes may have distinct metabolic vulnerabilities that can be exploited for therapeutic interventions. Here, the authors show that in lung cancer, genetic activation of distinct oncogenic receptor tyrosine kinases results in unique metabolic liabilities and, in particular, EGFR aberrant cancers rely on the serine biosynthetic pathway while FGFR aberrant cancers rely on glycolysis.

Systematic characterizations of adipose regulatory T (T reg ) cell subsets and their phenotypes remain uncommon. Using single-cell ATAC-sequencing and paired single-cell RNA and T cell receptor (TCR) sequencing to map mouse adipose T reg cells, we identified CD73 hi ST2 lo and CD73 lo ST2 hi subsets with distinct clonal expansion patterns. Analysis of TCR-sharing data implied a state transition between CD73 hi ST2 lo and CD73 lo ST2 hi subsets. Mechanistically, we revealed that insulin signaling occurs through a HIF-1α–Med23–PPAR-γ axis to drive the transition of CD73 hi ST2 lo into a CD73 lo ST2 hi adipose T reg cell subset. T reg cells deficient in insulin receptor, HIF-1α or Med23 have decreased PPAR-γ expression that in turn promotes accumulation of CD73 hi ST2 lo adipose T reg cells and physiological adenosine production to activate beige fat biogenesis. We therefore unveiled a developmental trajectory of adipose T reg cells and its dependence on insulin signaling. Our findings have implications for understanding the dynamics of adipose T reg cell subsets in aged and obese contexts. Adipose tissue-resident regulatory T (T reg ) cells are important for maintaining normal metabolic function and adiposity. Li and colleagues demonstrate that insulin signaling directly controls adipose T reg cell development and functionality

Besides the conventional carbon sources, acetyl-CoA has recently been shown to be generated from acetate in various types of cancers, where it promotes lipid synthesis and tumour growth. The underlying mechanism, however, remains largely unknown. We find that acetate induces a hyperacetylated state of histone H3 in hypoxic cells. Acetate predominately activates lipogenic genes ACACA and FASN expression by increasing H3K9, H3K27 and H3K56 acetylation levels at their promoter regions, thus enhancing de novo lipid synthesis, which combines with its function as the metabolic precursor for fatty acid synthesis. Acetyl-CoA synthetases (ACSS1, ACSS2) are involved in this acetate-mediated epigenetic regulation. More importantly, human hepatocellular carcinoma with high ACSS1/2 expression exhibit increased histone H3 acetylation and FASN expression. Taken together, this study demonstrates that acetate, in addition to its ability to induce fatty acid synthesis as an immediate metabolic precursor, also functions as an epigenetic metabolite to promote cancer cell survival under hypoxic stress. Cancer cells under stress use acetate to maintain the acetyl-CoA pool and fuel lipid biosynthesis. Here, the authors show that acetate also promotes de novo lipid synthesis by increasing histone acetylation at the promoters of lipogenic enzymes ACACA and FASN , thus inducing their expression.

Cancer cells experience an increase in oxidative stress. The pentose phosphate pathway (PPP) is a major biochemical pathway that generates antioxidant NADPH. Here, we show that transketolase (TKT), an enzyme in the PPP, is required for cancer growth because of its ability to affect the production of NAPDH to counteract oxidative stress. We show that TKT expression is tightly regulated by the Nuclear Factor, Erythroid 2-Like 2 (NRF2)/Kelch-Like ECH-Associated Protein 1 (KEAP1)/BTB and CNC Homolog 1 (BACH1) oxidative stress sensor pathway in cancers. Disturbing the redox homeostasis of cancer cells by genetic knockdown or pharmacologic inhibition of TKT sensitizes cancer cells to existing targeted therapy (Sorafenib). Our study strengthens the notion that antioxidants are beneficial to cancer growth and highlights the therapeutic benefits of targeting pathways that generate antioxidants.

The AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis. Although much has been learned on how low energy status and glucose starvation activate AMPK, how AMPK activity is properly controlled in vivo is still poorly understood. Here we report that UHRF1, an epigenetic regulator highly expressed in proliferating and cancer cells, interacts with AMPK and serves to suppress AMPK activity under both basal and stressed conditions. As a nuclear protein, UHRF1 promotes AMPK nuclear retention and strongly suppresses nuclear AMPK activity toward substrates H2B and EZH2. Importantly, we demonstrate that UHRF1 also robustly inhibits AMPK activity in the cytoplasm compartment, most likely as a consequence of AMPK nucleocytoplasmic shuttling. Mechanistically, we found that UHRF1 has no obvious effect on AMPK activation by upstream kinases LKB1 and CAMKK2 but inhibits AMPK activity by acting as a bridging factor targeting phosphatase PP2A to dephosphorylate AMPK. Hepatic overexpression of UHRF1 showed profound effects on glucose and lipid metabolism in wild-type mice but not in those with the liver-specific knockout of AMPKα1/α2, whereas knockdown of UHRF1 in adipose tissue led to AMPK activation and reduced sizes of adipocytes and lipogenic activity, highlighting the physiological significance of this regulation in glucose and lipid metabolism. Thus, our study identifies UHRF1 as a novel AMPK gate-keeper with critical roles in cellular metabolism.

The risk of drug-induced liver injury (DILI) poses a major challenge for development of natural products derived from traditional Chinese medicines (NP-TCMs). It is urgent to find a new method for the safety assessment of the NP-TCMs. Recent study has reported an in vitro/in silico method to estimate the acceptable daily intake of hepatotoxic compounds using support vector machine (SVM) classifier and physiologically based pharmacokinetic (PBPK) modeling. However, this method is not suitable for estimating the dosing schedule of compounds which are administered in multiple daily doses. Thus, in this study, the method mentioned above was in particular optimized, and used to estimate the hepatotoxic plasma concentrations of 17 NP-TCMs. Additionally, the oral dosing schedules of the triptolide, emodin, matrine and oxymatrine were also predicted by the SVM classifier and PBPK modeling. The optimization included that: (1) in vitro cytotoxicity data of 28 training set compounds was optimized using benchmark concentrations (BMC) modeling; (2) AUC of the training set compound was used as the in vivo metric instead of Cmax to better reflect the total daily exposure of compounds which are administered in multiple daily doses; (3) using the mean AUC in plasma as in vivo metric and BMC value as in vitro metric could achieve the better toxicity separation index (0.962 vs. 0.938); (4) The TSI for Cmax and BMC values was 0.985 calculated in this study, and the results indicated that BMC modeling improved the separation performance. This optimized in vitro–in vivo extrapolation (IVIVE) workflow could extrapolate in vitro BMC to blood concentrations and the oral dosing schedule which are corresponding to certain risk of hepatotoxicity. The estimated safe dosing schedule of oxymatrine by this optimized method was close to the clinical recommended dosing regimen. The results indicate that the optimized method could be used to predict the dosing schedule of compounds administered in multiple daily doses, and our optimized workflow could be helpful for the safety assessment as well as the research and development on NP-TCMs.

Resveratrol (trans-3,5,4′-trihydroxystilbene, RES) is one of the most well-known natural products with numerous health benefits. To explore the nutraceutical potentials of some dietary RES derivatives including isorhapontigenin (trans-3,5,4′-trihydroxy-3′-methoxystilbene, ISO), oxyresveratrol (trans-3,5,2′,4′-tetrahydroxystilbene, OXY) and pterostilbene (trans-3,5-dimethoxy-4′-hydroxystilbene, PTS), their impacts on metabolism and health were assessed in Sprague Dawley rats after a two-week daily oral administration at the dose of 100 µmol/kg/day. Non-targeted metabolomic analyses were carried out with the liver, heart, brain and plasma samples using gas chromatography–tandem mass spectrometry (GC-MS/MS). Notable in vivo health benefits were observed, as the rats received ISO, PTS or RES showed less body weight gain; the rats received OXY or RES displayed healthier fasting blood glucose levels; while all of the tested stilbenes exhibited cholesterol-lowering effects. Additionally, many important metabolic pathways such as glycolysis, pentose phosphate pathway, tricarboxylic acid cycle and fatty acid oxidation were found to be modulated by the tested stilbenes. Besides the reaffirmation of the well-known beneficial effects of RES in diabetes, obesity, cardiovascular disease and Alzheimer’s disease, the metabolomic analyses also suggest the anti-diabetic, cardio-, hepato- and neuro-protective activities of ISO; the anti-diabetic, cardio-, hepato- and neuro-protective effects of OXY; and the anti-aging, anti-inflammatory, cardio-, hepato- and neuro-protective potential of PTS. Interestingly, although these stilbenes share a similar structure, their biological activities appear to be distinct. In conclusion, similarly to RES, ISO, OXY and PTS have emerged as promising candidates for further nutraceutical development.

Improving annotation accuracy, coverage, speed and depth of lipid profiles remains a significant challenge in traditional lipid annotation. We introduce LipidIN, an advanced framework designed for flash platform-independent annotation. LipidIN features a 168.5-million lipid fragmentation hierarchical library that encompasses all potential chain compositions and carbon-carbon double bond locations. The expeditious querying module achieves speeds exceeding one hundred billion queries per second across all mass spectral libraries. The lipid categories intelligence model is developed using three relative retention time rules, reducing false positive annotations and predicting unannotated lipids with a 5.7% estimated false discovery rate, covering 8923 lipids cross various species. More importantly, LipidIN integrates a Wide-spectrum Modeling Yield network for regenerating lipid fragment fingerprints to further improve accuracy and coverage with a 20% estimated recall boosting. We further demonstrate the utility of LipidIN in multiple tasks for lipid annotation and biomarker discovery in clinical cohorts. LipidIN is an advanced framework designed for flash platform-independent lipid annotation. Featuring a comprehensive 168.5-million lipid fragment library with the intelligent models, LipidIN improves annotation accuracy, speed, and coverage.