International Journal of Biological Sciences

Although a defective vitamin D pathway has been widely suspected to be associated in SARS-CoV-2 pathobiology, the status of the vitamin D pathway and vitamin D-modulated genes in lung cells of patients infected with SARS-CoV-2 remains unknown. To understand the significance of the vitamin D pathway in SARS-CoV-2 pathobiology, computational approaches were applied to transcriptomic datasets from bronchoalveolar lavage fluid (BALF) cells of such patients or healthy individuals. Levels of vitamin D receptor, retinoid X receptor, and CYP27A1 in BALF cells of patients infected with SARS-CoV-2 were found to be reduced. Additionally, 107 differentially expressed, predominantly downregulated genes modulated by vitamin D were identified in transcriptomic datasets from patients cells. Further analysis of differentially expressed genes provided eight novel genes with a conserved motif with vitamin D-responsive elements, implying the role of both direct and indirect mechanisms of gene expression by the dysregulated vitamin D pathway in SARS-CoV-2-infected cells. Network analysis of differentially expressed vitamin D-modulated genes identified pathways in the immune system, NF-KB/cytokine signaling, and cell cycle regulation as top predicted pathways that might be affected in the cells of such patients. In brief, the results provided computational evidence to implicate a dysregulated vitamin D pathway in the pathobiology of SARS-CoV-2 infection.

BackgroundVisceral obesity is a critical determinant of severe coronavirus disease-2019 (COVID-19). Methods: In this study, we performed a comprehensive histomorphologic analysis of autoptic visceral adipose tissues (VAT), lungs and livers of 19 COVID-19 and 23 non-COVID-19 subjects. ResultsAlthough there were no between-groups differences in body-mass-index and adipocytes size, higher prevalence of CD68+ macrophages in COVID-19 subjects VAT was detected (p=0.005) and accompanied by crown-like structures presence, signs of adipocytes stress and death. Consistently, human adipocytes were successfully infected by SARS-CoV2 in vitro and displayed lower cell viability. Being VAT inflammation associated with lipids spill-over from dead adipocytes, we studied lipids distribution employing Oil-Red-O staining (ORO). Lipids were observed within lungs and livers interstitial spaces, macrophages, endothelial cells, and vessels lumen, features suggestive of fat embolism syndrome, more prevalent among COVID-19 individuals (p<0.001). Notably, signs of fat embolism were more prevalent among obese (p=0.03) independently of COVID-19 diagnosis, suggesting that such condition may be an obesity complication, exacerbated by SARS-CoV2 infection. Importantly, all infected subjects lungs presented lipids-rich (ORO+) hyaline membranes, formations associated with COVID-19-related pneumonia, present only in one control with non-COVID-19 pneumonia. ConclusionsThis study describes for the first time novel COVID-19-related features possibly underlying the unfavorable prognosis in obese SARS-CoV2-infected-subjects.

Coronavirus disease 2019 is a multi-systemic syndrome that caused a pandemic. Proteomic studies demonstrate changes in protein expression and interaction involved in signaling pathways related to SARS-CoV-2 infections. Protein phosphatases are important for cell signaling regulation. Here we aimed to understand the involvement of protein phosphatases and the signaling pathways that may be involved during SARS-CoV-2 infection. Then, we carried out a metanalysis of protein phosphatase interaction directly or indirectly with viral proteins. Additionally, we analyzed the expression degree of protein phosphatases, and phosphorylation degree of intermediate proteins. Our analyses revealed that PP2CA and PTEN were the key protein involved in the cell cycle and apoptosis regulation, during SARS-CoV-2 infection. Showing it as potential target for COVID-19 control.

PARK7, also known as DJ-1, plays a critical role in protecting cells by functioning as a sensitive oxidation sensor and modulator of antioxidants. DJ-1 acts to maintain mitochondrial function and regulate transcription in response to different stressors. In this study, we show that cell lines vary by their antioxidation potential at basal condition. The transcriptome of HEK293 cells was tested following knockdown (KD) of DJ-1 using siRNAs which reduced the DJ-1 transcripts to only 12% of the original level. We compared the expression levels of 14k protein coding transcripts, and 4.2k non-coding RNAs relative to control cells treated with non-specific siRNAs. Among the coding genes, [~]200 upregulated differentially expressed genes (DEGs) signified a coordinated antiviral innate immune response. Most genes were associated with regulation of type 1 interferons (IFN) and induction of inflammatory cytokines. About a quarter of these genes were also induced in cells treated by non-specific siRNAs that were used as a negative control. Beyond the antiviral response, 114 genes were specific to KD of DJ-1 with enrichment in RNA metabolism and mitochondrial functions. A smaller set of downregulated genes (58 genes) were associated with dysregulation in membrane structure, cell viability, and mitophagy. We propose that KD of DJ-1 diminish its protective potency against oxidative stress, rendering the cells labile and responsive to dsRNA signal by activation of a large number of genes, many of which drive apoptosis, cell death, and inflammatory signatures. The KD of DJ-1 highlights its crucial role in regulating genes associated with antiviral responses, RNA metabolism, and mitochondrial functions, apparently through alteration in STAT activity and downstream signaling. Given that DJ-1 is highly expressed in metastatic cancers, targeting DJ-1 could be a promising therapeutic strategy where manipulation of DJ-1 level may reduce cancer cell viability and enhance the efficacy of cancer treatments.

Cancer cachexia is one of the most common causes of death among cancer patients, no effective anti-cachectic treatment is currently available. In experimental cachectic models, aberrant activation of STAT3 in skeletal muscle has been found to contribute to muscle wasting. However, its clinical association, the factors regulating STAT3 activation, and the molecular mechanisms of STAT3-induced muscle atrophy in cancer cachexia remain incompletely understood. Here, we show that an enhanced interaction between STAT3 and HSP90, which causes the persistent STAT3 activation in the skeletal muscle of cancer cachexia patients, is the crucial event for the development of cachectic muscle wasting. Administration of HSP90 inhibitors alleviated the muscle wasting in C26 tumor-bearing cachetic mice model or C26 conditional medium induced C2C12 myotube atrophy. A mechanistic study indicated that in cachectic skeletal muscle, prolonged STAT3 activation triggered muscle wasting in a FOXO1-dependent manner, STAT3 activated FOXO1 by binding directly to its promoter. Our results provide key insights into the role of the HSP90/STAT3/FOXO1 axis in cachectic muscle wasting, which shows promising therapeutic potential as a target for the treatment of cancer cachexia.

CIgG has received increasing attention, and was first discovered by our group to indicate poor prognosis in glioma. Furthermore, by protein mass spectrometry, we found that FCGRT can combine with CIgG. However, the study of FCGRT in glioma has not been reported. We used the CGGA325, TCGA dataset and immunohistochemistry to verify the importance of FCGRT on the prognosis of glioma patients. Single cell sequencing data analysis evaluated that the role of FCGRT in the microenvironment of glioma. Estimate, ssGSEA, EPIC and xCell were used for immune infiltration analysis. FCGRT was knocked down in U251 cells to detect the effect of FCGRT on the malignant development of glioma. These results showed that patients with higher FCGRT expression had a shorter overall survival. FCGRT was closely related to the tumor microenvironment, especially to macrophages in the tumor microenvironment (r=0.743, p<0.001). Interestingly we also found that FCGRT was positively correlated with IGHG1. Finally, we found that knock-down of FCGRT resulted in a decrease in proliferation, migration and invasion of U251 cells. Taken together, we believe that FCGRT is an independent prognostic factor for glioma patients, and its possible mechanism is to promote proliferation and invasion of tumor cells by interacting with CIgG.

Background & AimsHepatic gluconeogenesis is pathologically elevated in type 2 diabetes (T2DM). Although the PKA/CREB axis is a central regulator, the mechanisms fine-tuning its activity, particularly nuclear events, remain elusive. This study investigates the role of the inner nuclear membrane protein SAMP1/TMEM201 in this process. MethodsSAMP1 expression was assessed in diabetic (db/db) mice. Gain- and loss-of-function studies were performed in vivo (via AAV8-mediated hepatocyte-specific manipulation in mice) and in vitro (in primary mouse hepatocytes). Mechanisms were probed using co-immunoprecipitation, Western blotting, ELISA, and pharmacological inhibition. ResultsHepatic SAMP1 was upregulated in db/db mice. Overexpression of SAMP1 exacerbated hyperglycemia and glucose intolerance, enhanced gluconeogenic gene expression (Pck1, G6pc), and increased glucose output. Conversely, SAMP1 knockdown attenuated these effects. Mechanistically, SAMP1 interacted with Importin, facilitating its nuclear translocation. This led to enhanced CREB phosphorylation and activation of gluconeogenic genes, an effect abolished by the CREB inhibitor KG-501. ConclusionsSAMP1 is a novel critical enhancer of hepatic gluconeogenesis. It functions by promoting Importin-mediated nuclear import of PKA, thereby amplifying the PKA/CREB pathway. Targeting SAMP1 represents a promising strategy for curbing excessive hepatic glucose production in T2DM.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, often developing in the context of chronic liver disease, fibrosis, and cirrhosis. Identifying novel biomarkers with diagnostic and therapeutic potential is essential, particularly those relevant across multiple cancer types. This study integrates single-cell RNA sequencing (scRNA-seq) data from healthy and diseased liver tissues, analyzing different cellular lineages to identify genes involved in fibrosis, angiogenesis, immune modulation, and apoptosis regulation. Uniform Manifold Approximation and Projection (UMAP) clustering, differential gene expression (DEG) analysis, and protein-protein interaction (PPI) network construction were employed to identify genes contributing to tumor progression and metabolic reprogramming. Key genes, including Transmembrane BAX Inhibitor Motif Containing 4 (TMBIM4), Regulator of G-protein signaling 5 (RGS5), CEA Cell Adhesion Molecule 7 (CEACAM7), and Variable Charge X-Linked 2 (VCX2), exhibited significant roles in tumorigenesis and chromosomal stability. VCX2, a cancer/testis antigen, emerged as a potential biomarker and druggable target due to its altered expression among multiple cancers. Structural modeling and molecular docking (MD) of VCX2 identified a high affinity binding pocket, guiding a virtual screening of Peruvian natural products. Luteolin-5-O-glucoside, from Equisetum arvense, was identified as the most promising compound, showing a strong docking score (-7.42 kcal/mol) and favorable binding free energy ({Delta}G_bind = -40.13 kcal/mol). MMGBSA calculations revealed stabilizing hydrogen bonds with PRO91, GLU97, and GLU109, reinforcing its strong binding stability. These findings position VCX2 as a promising target for HCC therapy and suggest Luteolin-5-O-glucoside as a lead compound with high drug-like potential. Further studies should focus on experimental validation, molecular dynamics simulations, and structure-activity relationship (SAR) optimization to advance VCX2-targeted therapies. Highlight statementsO_LIVCX2 as a Biomarker exhibited differential expressions in HCC versus healthy liver tissue and a suggested role in tumor progression and chromosomal stability. C_LIO_LILuteolin-5-O-glucoside from Equisetum arvense was identified as a promising compound: strong docking score (-7.42 kcal/mol), favorable binding free energy ({Delta}G_bind = -40.13 kcal/mol), and stabilized interactions with key amino acids (PRO91, GLU97, GLU109). C_LIO_LIVCX2 may serve as an oncogenic driver; small molecule inhibition could desensitize tumor cells that need further refinement and validation of structural models due to lack of experimentally resolved crystal structure. C_LIO_LIVCX2 is a novel biomarker and drug target for HCC with Luteolin-5-O-glucoside presents potential for targeted therapy, paving the way for precision medicine approaches. C_LI

Osteoarthritis (OA) is a progressive degenerative joint disorder characterized by cartilage degradation, chronic pain, and impaired joint function. The avascular nature of cartilage isolates chondrocytes from systemic circulation, presenting significant challenges for therapeutic intervention. Despite extensive efforts, no clinically effective disease-modifying osteoarthritis drugs (DMOADs) are currently available. Targeting chondrocyte-specific receptors has therefore emerged as a promising strategy. The osteoclast-associated receptor (OSCAR), expressed on chondrocytes, has been implicated in the regulation of cartilage homeostasis and OA pathogenesis. Here, we applied sBEAR (Structurally similar Bioactive compound Enrichment by Assay Repositioning), a bioactivity-driven virtual screening framework independent of target structural information, to identify small-molecule inhibitors of the OSCAR-collagen interaction. By mining large-scale bioactivity profiles, we identified adefovir (ADV) and brivudine (BRV), as candidate OSCAR inhibitors. Molecular docking analyses indicated that both compounds occupy the collagen-recognition pocket within the OSCAR D2 domain. Intra-articular administration of these compounds in a post-traumatic OA mouse model significantly attenuated OA progression and enhanced chondrocyte regeneration. Both compounds increased Sox9 expression, and transcriptomic analyses revealed that BRV reverses inflammatory and extracellular matrix-degrading transcriptional programs. Together, these findings establish OSCAR as a therapeutically actionable target in OA and highlight ADV and BRV as potential DMOAD candidates.

Respiratory syncytial virus (RSV) is a major cause of severe respiratory infections, yet effective treatments are lacking. We found that the molecular chaperon DNAJB6/MRJ plays an essential role in RSV replication. Depletion of the long isoform of MRJ (MRJ-L) suppresses RSV replication. Transcriptomic analysis revealed that MRJ-L depletion downregulates Wnt signaling pathways. A pharmacological inhibitor of Wnt signaling suppressed RSV propagation and unexpectedly reduced MRJ-L expression, suggesting a positive regulatory loop between Wnt signaling and MRJ-L expression. Notably, simultaneous inhibition of Wnt signaling and MRJ-L additively suppressed RSV replication, suggesting that the Wnt-MRJ-L axis may serve as a new therapeutic target. This study provides insights into host-RSV interactions and potential antiviral strategies. Author SummaryThe molecular chaperone DNAJB6/MRJ has been implicated in the replication of respiratory syncytial virus (RSV), although the precise mechanisms remain unclear. In this study, we discovered that MRJ may influence RSV replication via Wnt signaling pathways. Specifically, we demonstrated that Wnt signaling inhibitor Wnt-C59 significantly reduced RSV replication by suppressing the synthesis of viral mRNA and genome/antigenome. Moreover, a positive feedback loop of the Wnt-MRJ axis may play a critical role in regulating RSV replication. Importantly, RSV replication was suppressed additively by inhibition of Wnt signaling and depletion of MRJ-L. Thus, a dual-targeted therapeutic approach may be effective in combating RSV infections.

BackgroundLumbar disc degeneration (LDD) is characterized by chronic inflammation, oxidative stress, and extracellular matrix (ECM) breakdown, yet current therapies provide only symptomatic relief. Xiaobi Plaster (XBG), a traditional Chinese transdermal herbal preparation, has shown clinical benefit, but its molecular mechanisms remain unclear. MethodsWe applied an integrative systems biology framework combining network pharmacology, machine learning, and transcriptomic validation to identify candidate targets of Xiaobi Plaster in LDD. Molecular docking, dynamics simulations, and immune infiltration analysis further elucidated the underlying mechanisms, which were experimentally validated in a rat puncture-induced degeneration model. ResultsThree key targets--AHR, PTPN2, and SOAT1--were identified, with AHR emerging as the central regulator. Differential expression and enrichment analyses highlighted inflammatory and ECM-remodeling pathways, which overlapped with AHR-specific GSEA, underscoring its hub role in integrating immune and redox signaling with matrix turnover. Molecular docking and 100-ns molecular dynamics confirmed rutaecarpine (MOL002662) as the most stable AHR ligand. Transcriptomic data further showed AHR expression correlates with degeneration severity and mast cell infiltration. In vivo qPCR and Western blotting validated upregulation of AHR and supporting roles of PTPN2 and SOAT1 in degenerative discs. ConclusionThis study elucidates the multi-target and multi-pathway mechanisms of XBG in LDD, highlighting AHR as a pivotal therapeutic target modulated by rutaecarpine, with PTPN2 and SOAT1 serving as auxiliary regulators. These findings provide mechanistic insights into the transdermal application of XBG and support the therapeutic relevance of targeting the AHR signaling axis in LDD.

Severe manifestations of COVID-19 are mostly restricted to people with comorbidities. Here we report that induced mild pulmonary morbidities render SARS-CoV-2-refractive CD-1 mice to be susceptible to this virus. Specifically, SARS-CoV-2 infection after application of low-doses of the acute-lung-injury stimulants bleomycin or ricin caused a severe disease in CD-1 mice, manifested by sustained body weight loss and mortality rates of >50%. Further studies revealed markedly higher levels of viral RNA in the lungs, heart and serum of low-dose-ricin pretreated, as compared to non-pretreated mice. Notably, the deleterious effects of SARS-CoV-2 infection were effectively alleviated by passive transfer of polyclonal or monoclonal antibodies generated against SARS-CoV-2 RBD. Thus, viral cell entry in the sensitized mice seems to involve viral RBD binding, albeit by a mechanism other than the canonical ACE2-mediated uptake route. In summary, we present a novel mice-based animal model for the study of comorbidity-dependent severe COVID-19.

The human DNA repair enzyme AlkB homologue-2 and 3 (ALKBH2 and ALKKBH3) repairs methyl adducts from genomic DNA. Overexpression of ALKBH2 and ALKBH3 has been implicated in both tumorigenesis and chemotherapy resistance in some cancers, including glioblastoma and renal cancer rendering it a potential therapeutic target and a diagnostic marker. However, no inhibitor is available against these important DNA repair proteins. Intending to repurpose a drug as an inhibitor of ALKBH2/ALKBH3, we performed in silico evaluation of HIV protease inhibitors and identified Ritonavir as an ALKBH2-interacting molecule. Using molecular dynamics simulation, we elucidated the molecular details of Ritonavir-ALKBH2 interaction. The present work highlights that Ritonavir might be used to target the ALKBH2-mediated DNA alkylation repair.

Osteoarthritis (OA) is the most common joint disease worldwide and a leading cause of disability. The Wnt/{beta}-catenin cascade is essential in articular cartilage development and homeostasis. It has proved that both overexpression and loss of {beta}-catenin lead to cartilage degeneration and OA symptoms. However, the mechanism of Wnt/{beta}-catenin balance in healthy cartilage remains unclear. In the present work, we confirmed that the Wnt/{beta}-catenin activation and PTHrP suppression in cartilage during the post-traumatic OA process. Then, we demonstrated that Wnt/{beta}-catenin upregulated PTHrP expression through binding to its promoter (P2), and induce mRNA (AT6) transcript expression, while PTHrP repressed Wnt/{beta}-catenin activity, and formed a Wnt/{beta}-catenin-PTHrP negative feedback loop in the very primary chondrocytes to maintain cartilage homeostasis. However, this negative feedback loop vanished in dedifferentiated chondrocytes, hypertrophic chondrocytes, and IL-1{beta} treated very primary chondrocytes. We further found that miR-106b-5p was increased in these "aberrant" chondrocytes and directly targeted PTHrP mRNA to abolish the feedback loop. PKC-{zeta} was activated by PTHrP through phosphorylation at Thr410/403, and subsequently induced {beta}-catenin phosphorylation and ubiquitination. Finally, we disclosed that exogenous PTHrP attenuated OA progression exogenous PTHrP attenuated OA progression. Together, these findings reveal that PTHrP is a vital mediator to keep Wnt/{beta}-catenin activity homeostasis in healthy cartilage through a negative feedback loop, and PTHrP might be a therapeutic target for OA and cartilage regeneration.

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood characterized by the inability to exit the proliferative myoblast-like stage. The alveolar fusion positive subtype (FP-ARMS) is the most aggressive and is mainly caused by the expression of PAX3/7-FOXO1 oncoproteins, which are challenging pharmacological targets. Thus, other therapeutic vulnerabilities resulting from gene expression changes are progressively being recognized. Here, we identified the DEAD box RNA helicase 5 (DDX5) as a potential therapeutic target to inhibit FP-ARMS growth. We show that DDX5 is overexpressed in alveolar RMS cells, demonstrating that its depletion drastically decreases FP-ARMS viability and slows tumor growth in xenograft models. Mechanistically, we provide evidence that DDX5 functions upstream the G9a/AKT survival signalling pathway, by modulating G9a protein stability. Finally, we show that G9a interacts with PAX3-FOXO1 and regulates its activity, thus sustaining FP-ARMS myoblastic state. Together, our findings identify a novel survival-promoting loop in FP-ARMS and highlight DDX5 as potential therapeutic target to arrest rhabdomyosarcoma growth.

Withdrawal StatementThe authors have withdrawn their manuscript owing to the inability to complete the revisions or follow up on the manuscript at this time, due to personal circumstances. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

BackgroundThyroid eye disease (TED) is a debilitating autoimmune disorder affecting 25-50% of patients with Graves disease. TED is characterized by inflammation and tissue remodeling of orbital tissues. Orbital fibroblasts (OFs) and platelet-derived growth factor (PDGF) signaling promote tissue remodeling in TED. While metformins therapeutic potential has been proposed in various inflammatory conditions, its role in modulating PDGF signaling in TED remains unexplored. MethodsOFs were isolated from TED (n= 14) and non-TED subjects (n=4). OFs were treated with PDGF{beta} (25 ng/mL) and/or AMPK activators metformin (1-5 mM) and AICAR (0.4-1 mM). Hyaluronan (HA) production was assessed via agarose gel electrophoresis and ELISA. Inflammatory mediators (IL6 and IL8) were measured by ELISA. Protein expression and signaling pathways were analyzed by Western blot. ResultsTED OFs showed enhanced HA synthesis ([~]3-fold increase) and IL6 and IL8 responses to PDGF{beta}. PDGF{beta} treatment suppressed AMPK phosphorylation in a dose-dependent manner. Metformin increased AMPK phosphorylation (3.2-fold) and decreased IL6 and IL8 production. Both metformin and AICAR attenuated PDGF{beta}-induced HA production (56-68% reduction), IL6 ([~]50% reduction), and IL8 ([~]65% reduction) production in TED OFs. ConclusionsThis study demonstrates that PDGF{beta} suppresses AMPK signaling while AMPK activation by metformin counters PDGF{beta}-induced responses. These findings suggest that metformin is a potential therapeutic option for TED through modulation of HA and inflammatory cytokine production.

Objectives; The role of nuclear receptor subfamily 4, group A, member 3 (NR4A3) in hepatic steatosis, inflammation, and insulin resistance (IR) within the context of metabolic dysfunction-associated steatotic liver disease (MASLD) remains largely underexplored. Consequently, this study aimed to examine NR4A3's impact on MASLD and the potential underlying mechanisms. Methods; We aimed to elucidate the functional role of NR4A3 in MASLD through its knockdown in cell culture and animal models. To establish the cell culture model of MASLD, LO2 cells were treated with free fatty acids (FFAs), while male C57BL/6 mice were fed a high-fat diet (HFD) to create the animal model. NR4A3 knockdown was achieved using specific short hairpin RNA (NR4A3-shRNA) in the mice model and three small interfering RNAs (NR4A3-siRNAs) in the cell culture model. The lipids content, fatty acid synthesis, inflammatory factors, and IR were then assessed with and without NR4A3 knockdown. Furthermore, the underlying mechanism through which NR4A3 exerts its influence was explored by analyzing the interaction between NR4A3 and activating transcription factor 3 (ATF3). Results: In the cell culture experiments, the knockdown of NR4A3 significantly decreased the lipids content, fatty acid synthesis, and inflammatory factors in the LO2 cells treated with FFAs in the NR4A3-shRNA group compared with those in the NC-shRNA control group. In the animal model experiments, NR4A3 knockdown in the HFD male C57BL/6 mice significantly ameliorated HFD-induced hepatic steatosis, inflammation, and IR. Mechanistically, the knockdown of NR4A3 downregulated the expression and transcriptional activity of ATF3, resulting in an impaired ATF3 function. ATF3 overexpression significantly reversed lipid accumulation decline and reduced inflammation after NR4A3 knockdown. Conclusion: The downregulation of NR4A3 alleviates MASLD by modulating ATF3, suggesting this may be a promising therapeutic target.

Oxidative phosphorylation (OXPHOS) is a vital pathway provides ATP for intracellular activities. Here, we found that Hantaan virus (HTNV) exploited mitochondria OXPHOS to assist its replication in host cells and Protein Kinase B/AKT played a major function in this process. Inhibiting AKT activation by BEZ treatment can inhibit HTNV replication and prevent the increase of OXPHOS level caused by HTNV infection. We also found that HTNV infection can promote AKT translocation to mitochondria, where AKT phosphorylates Polynucleotide phosphorylase (PNPT). Taken together, our research demonstrates that HTNV replication exploits OXPHOS in host cells and it increases OXPHOS function by AKT-PNPT interaction in mitochondria. IMPORTANCEVirus depends on metabolic pathways in host cells to favor its replication. This is a vital process which needs complicated host-virus interaction and targeting this process is a new strategy for antiviral drug development. Hantaan virus (HTNV) is the major pathogen which causes Hemorrhagic Fever with Renal Syndrome (HFRS) in China. However, there are neither effective therapeutic drugs nor FDA-licensed vaccine against HFRS, a deeper understanding of HTNV infection characteristics is of great significance for global public health and safety. This research means to elucidate the major metabolic pathway exploited by HTNV during its replication in host cells and its underlying molecular mechanism, which can enrich our understanding about HTNV biological characteristics and pathogenesis, also provide a new view on anti-HTNV drug development.

The FDA-approved oral multi-kinase inhibitor, sorafenib (BAY 43-9006, Nexavar), is the first approved systemic therapy for patients with unresectable hepatocellular carcinoma (HCC). Although it has been shown to significantly improve the overall survival of patients with HCC, drug resistance limits the response rate to this therapeutic. Here, we report that acquired sorafenib resistance is associated with overexpression of the deacetylase, SIRT7, and a high level of ERK phosphorylation. Further, we identify that the hyperactivation of ERK is controlled by SIRT7-mediated deacetylation of DDX3X. The inhibition of SIRT7 combined with sorafenib resulted in a marked reduction of cell viability in vitro and of tumor growth in vivo. It seems plausible that SIRT7 is responsible for the acquired sorafenib resistance and its inhibition is most likely beneficial together in conjunction with sorafenib by suppressing ERK signaling. HighlightsO_LISorafenib resistance in HCC is associated with SIRT7 and ERK hyperactivation. C_LIO_LISuppression of SIRT7 combined with sorafenib restores sensitivity to sorafenib. C_LIO_LISIRT7 controls sorafenib resistance through ERK activation by mediating DDX3X deacetylation. C_LI