BACKGROUND:Subarachnoid haemorrhage (SAH), a devastating subtype of stroke, is predominantly caused by the rupture of intracranial aneurysms. Emerging evidence indicates that the risk of intracranial aneurysm rupture correlates with elevated serum levels of fatty acids and pro-inflammatory cytokines. Moreover, increased serum concentrations of adipocyte fatty acid-binding protein (A-FABP), an inflammation-related adipokine, have been associated with poorer prognosis in SAH. However, the precise roles of A-FABP in SAH pathogenesis and its biomarker potential in cerebrospinal fluid (CSF) remain unclear. METHODS:CSF from 40 SAH patients and 30 controls was analysed by targeted fatty acid metabolomics. Experimental SAH mice were induced by endovascular perforation in both genetic deletion and pharmacological inhibition of A-FABP. Brain injury was quantified by neurobehavioural test, inflammatory cytokine expression and TUNEL staining. In vitro, conditioned medium from fatty acid-stimulated microglia was applied to primary neurons to evaluate apoptosis. Microglial metabolic reprogramming was assayed with Seahorse XF assays. RESULTS:CSF revealed significant metabolic disruption in SAH, characterized by arachidonic acid (AA), linoleic acid and palmitic acid (PA). Enrichment analysis implicated A-FABP plays a crucial role in SAH pathogenesis. Notably, elevated A-FABP levels independently predicted increased SAH severity and poorer prognosis. In mice model of SAH, A-FABP was significantly upregulated in microglia. Genetic deletion and pharmacological inhibition of A-FABP significantly ameliorated brain injury, including neurological deficits, neuroinflammation and neuronal apoptosis. Mechanistically, PA and AA promoted BV2 microglial inflammation via an A-FABP-dependent manner, subsequently inducing apoptosis in co-cultured primary neurons. Moreover, A-FABP inhibition reprogrammed microglial metabolism, enhancing fatty acid β-oxidation and energy supply. Proteomics further identified the JAK2/STAT3 as a downstream pathway of A-FABP-mediated neuroinflammation. CONCLUSIONS:A-FABP is a promising biomarker and translatable therapeutic target to improve SAH outcome. Targeting A-FABP disrupts fatty acids-driven neuroinflammation and microglial metabolic reprogramming to reduce brain injury after SAH.

Abstract Background Stress hyperglycemia ratio (SHR) represents the degree of acute glycemic stress relative to chronic glycemic control. Although SHR has been proposed as a better prognostic marker than absolute glucose levels, its quantitative relationship with in-hospital mortality in acute myocardial infarction (AMI) remains uncertain. Methods A systematic search of PubMed, Embase, Web of Science, and the Cochrane Library was conducted up to August 10, 2025. Observational studies reporting the association between SHR and in-hospital mortality in AMI were included. Quality assessment was performed using the Newcastle–Ottawa Scale. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with a random-effects model. The dose–response relationships were analyzed using the Greenland and Longnecker method and restricted cubic spline models. Results Eleven studies involving 27,343 patients were included. Higher SHR was significantly associated with increased in-hospital mortality (pooled OR = 2.14; 95% CI: 1.74–2.55; I² = 63%; P < 0.001). The association remained basically consistent across subgroups and sensitivity analysis. Furthermore, the restricted cubic spline model illustrated a non-linear dose-response association between SHR and in-hospital mortality. Conclusions In patients with AMI, an elevated SHR is consistently and non-linearly associated with a higher risk of in-hospital mortality. These findings suggest that SHR may serve as a valuable prognostic tool for early risk stratification, although further prospective studies are needed to confirm its clinical utility.

Dysregulation of adipose tissue (AT) homeostasis in obesity contributes to metabolic stress and disorders. Here, we identified that Coiled-coil-helix-coiled-coil-helix domain containing 10 (Chchd10) is a novel regulator of AT remodeling upon excess energy intake. Chchd10 is significantly reduced in the white adipose tissue (WAT) of mice in response to high-fat diet (HFD) feeding. AT-Chchd10 deficiency accelerates adipogenesis predominantly in subcutaneous AT of mice to store excess energy in response to short-term HFD feeding while upregulates glutathione S-transferase A4 (GSTA4) to facilitate 4-HNE clearance mainly in visceral AT to prevent protein carbonylation-induced cell dysfunction after long-term HFD feeding. Hence, Chchd10 deficiency attenuates diet-induced obesity and related metabolic disorders in mice. Mechanistically, Chchd10 deficiency enhances adipogenesis and GSTA4 expression by activating TDP43/Raptor/p62/Keap1/NRF2 axis. Notably, the beneficial effect of Chchd10 deficiency is eliminated in hypertrophic adipocytes, where p62 is strikingly reduced. Collectively, Chchd10 is a metabolic sensor maintaining AT homeostasis, and the loss of p62 in adipose tissue under obese conditions impairs Chchd10-mediated AT remodeling.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor with poor prognosis. A better understanding of mechanisms concerned in glioma invasion might be critical for treatment optimization. Given that epithelial-mesenchymal transition in tumor cells is closely associated with glioma progression and recurrence, identifying pivotal mediators in GBM EMT process is urgently needed. As a member of Fatty acid binding protein (FABP) family, FABP4 serves as chaperones for free fatty acids and participates in cellular process including fatty acid uptake, transport, and metabolism. In this study, our data revealed that FABP4 expression was elevated in human GBM samples and correlated with a mesenchymal glioma subtype. Gain of function and loss of function experiments indicated that FABP4 potently rendered glioma cells increased filopodia formation and cell invasiveness. Differential expression genes analysis and GSEA in TCGA dataset revealed an EMT-related molecular signature in FABP4-mediated signaling pathways. Cell interaction analysis suggested CD36 as a potential target regulated by FABP4. Furthermore, in vitro mechanistic experiments demonstrated that FABP4-induced CD36 expression promoted EMT via non-canonical TGFβ pathways. An intracranial glioma model was constructed to assess the effect of FABP4 on tumor progression in vivo. Together, our findings demonstrated a critical role for FABP4 in the regulation invasion and EMT in GBM, and suggest that pharmacological inhibition of FABP4 may represent a promising therapeutic strategy for treatment of GBM.

Autophagy is an intracellular, self-degradative process that serves the cell energy sources balance and tissue homeostasis, and is critical in multiple myeloma (MM) pathogenesis, however, the prognostic role of autophagy-related genes (ARGs) in MM remains undefined. In the present study, ARGs were selected from Gene Expression Omnibus datasets containing 1038 samples from patients with MM. Furthermore, an autophagy risk score (ARS) model was developed using Cox regression analysis. Patients with MM could be stratified into high- and low-risk groups with distinct clinical outcomes by ARS. Moreover, we established a nomogram, including the independent prognostic factor ARS and the International Staging System, which can improve the prognostic performance of MM. Gene Ontology analysis revealed that most of pathways enriched for ARGs were related to autophagy and metabolism. Furthermore, the critical role of ARNT-mediated autophagy in MM cell proliferation and drug resistance were validated using in vivo and in vitro strategies. Mechanistically, ARNT expresses in various immune cells in the bone marrow microenvironment, forming a positive feedback loop with hypoxia. Moreover, ARNT exacerbates autophagy through activating AKT signaling pathway. In conclusion, this study constructed an ARG-based prognostic model to predict the prognosis of patients with MM and revealed that targeting specific autophagy genes may provide potential insights relevant to MM treatment.

Upregulation of metabolism-related gene cytidine triphosphate synthase 1 (CTPS1) is associated with poor prognosis in multiple myeloma (MM). However, its role in MM remains unclear. In this study, bioinformatics analysis revealed significant differences in CTPS1 expression levels among various plasma cell malignancies. The patients with high CTPS1 expression had poor overall survival, progression-free survival, and event-free survival. CTPS1 was significantly correlated with sex, albumin, β2 microglobulin, lactate dehydrogenase, and advanced disease. In vitro experiments demonstrated that CTPS1-overexpressing (CTPS1-OE) cells proliferated faster than CTPS1-short hairpin RNA (CTPS1-sh) cells. NRG-SGM3 mice showed significantly accelerated tumor growth in the CTPS1-OE group. CTPS1-OE decreased sensitivity to bortezomib, whereas CTPS1-sh increased sensitivity to bortezomib in MM cell lines. Mechanistically, CTPS1 was primarily involved in metabolism processes. Additionally, CTPS1 was closely related to several co-expressed genes such as MYC and the bone marrow immune microenvironment. In conclusion, CTPS1 is a significant prognostic biomarker for patients with MM, suggesting a potential therapeutic target.

Interferon-induced transmembrane protein 3 (IFITM3) has been previously verified to be an endosomal protein that prevents viral infection. Recent findings suggested IFITM3 as a key factor in tumor invasion and progression. To clarify the role and molecular mechanism of IFITM3 in Glioblastoma multiforme (GBM) progression, we investigated the expression of IFITM3 in glioma datasets culled from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA). Primary GBM stem cells (GSCs) were cultured and identified in vitro. Loss-of-function and gain-of-function experiments were established by using shRNAs and lentiviral vectors targeting IFITM3. Co-culture system of GSCs and vascular endothelial cells was constructed in a Transwell chamber. Tube formation and spheroid-based angiogenesis assays were performed to determine the angiogenic capacity of endothelial cells. Results revealed that IFITM3 is elevated in GBM samples and predictive of adverse outcome. Mechanistically, GSCs-derived IFITM3 causes activation of Jak2/STAT3 signaling and leads to robust secretion of bFGF into tumor environment, which eventually results in enhanced angiogenesis. Taken together, these evidence indicated IFITM3 as an essential factor in GBM angiogenesis. Our findings provide a new insight into mechanism by which IFITM3 modulates GBM angiogenesis.

Type 1 diabetes (T1D) is a chronic disease characterized by self-destruction of insulin-producing pancreatic β cells by cytotoxic T cell activity. However, the pathogenic mechanism of T cell infiltration remains obscure. Recently, tissue-resident memory T (TRM) cells have been shown to contribute to cytotoxic T cell recruitment. TRM cells are found present in human pancreas and are suggested to modulate immune homeostasis. Here, the role of TRM cells in the development of T1D is investigated. The presence of TRM cells in pancreatic islets is observed in non-obese diabetic (NOD) mice before T1D onset. Mechanistically, elevated fatty acid-binding protein 4 (FABP4) potentiates the survival and alarming function of TRM cells by promoting fatty acid utilization and C-X-C motif chemokine 10 (CXCL10) secretion, respectively. In NOD mice, genetic deletion of FABP4 or depletion of TRM cells using CD69 neutralizing antibodies resulted in a similar reduction of pancreatic cytotoxic T cell recruitment, a delay in diabetic incidence, and a suppression of CXCL10 production. Thus, targeting FABP4 may represent a promising therapeutic strategy for T1D.

Background Metabolic reprogramming is a hallmark of cancer progression and holds great significance for the tumor microenvironment (TME). Lactate, as an abundant metabolite, has been found to play a critical role in the development of cancer and in the immunosuppression of TME. However, the potential role of lactate metabolism-related genes in multiple myeloma (MM) remains unclear. Methods RNA sequencing data and clinical information of multiple myeloma (MM) were obtained from The Cancer Genome Atlas (TCGA) database. Lactate metabolism-related genes (LMRGs) were sourced from Molecular Signature Database v7.4, and then compared with the candidate genes from TCGA to obtain the final gene set. Prognostic genes were screened using univariate analysis and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression. A lactate metabolism-related risk profile was constructed using multivariate Cox regression analysis. The signature was validated by time-dependent ROC curve analysis and Kaplan-Meier analysis. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway functional analysis were performed to compare high-risk groups with low-risk groups. CCK8 assays were utilized to assess the proliferation ability of MM cells. Transwell assay was employed to detect their migration ability. Intracellular lactate content as well as glucose content was measured to evaluate lactate metabolism levels. Loss or gain-of-function studies were carried out using shRNA knockdown or lentiviral transduction strategies in order to investigate the precise role of LMRGs in MM. Results We developed a risk signature based on 18 LMRGs. Kaplan-Meier curves confirmed that the high-risk group exhibited a poorer prognosis compared to the low-risk group. Subsequently, a nomogram was constructed to predict the probability of MM survival. Additionally, we conducted GO enrichment analysis and KEGG pathway functional analysis between the high and low-risk groups, which revealed significant associations with immune regulation and energy metabolism. Furthermore, we demonstrated that one of the lactate metabolism-related genes, JAMIP2, could promote myeloma cell proliferation, migration, and lactate metabolism via activating PI3K-Akt signaling pathway. Conclusion In conclusion, this study identified and constructed LMRGs in MM, which showed high diagnostic accuracy in predicting OS in MM patients and linked to immunity and drug sensitivity. JAMIP2, which was identified as a novel molecule mediating lactate metabolism, promoted MM cell proliferation, migration and lactate metabolism through PI3K-Akt signaling pathway. Future studies are expected to validate the utility of the constructed LMRGs in MM patients.

Acute myeloid leukemia (AML) is the type of hematologic neoplasm most common in adults. Glucocorticoid-induced gene TSC22D3 regulates cell proliferation through its function as a transcription factor. However, there is no consensus on the prognostic and immunoregulatory significance of TSC22D3 in AML. In the present study, we evaluated the correlation between TSC22D3 expression, immunoinfiltration, and prognostic significance in AML. Knockdown of TSC22D3 significantly attenuated the proliferation of Hel cells and increased sensitivity to cytarabine (Ara-c) drugs. Furthermore, TSC22D3 reduced the release of interleukin-1β (IL-1β) by inhibiting the NF-κB/NLRP3 signaling pathway, thereby inhibiting macrophage polarization to M1 subtype, and attenuating the pro-inflammatory tumor microenvironment. In conclusion, this study identified TSC22D3 as an immune-related prognostic biomarker for AML patients and suggested that therapeutic targeting of TSC22D3 may be a potential treatment option for AML through tumor immune escape.

Lymph nodes (LNs) are always embedded in the metabolically-active white adipose tissue (WAT), whereas their functional relationship remains obscure. Here, we identify fibroblastic reticular cells (FRCs) in inguinal LNs (iLNs) as a major source of IL-33 in mediating cold-induced beiging and thermogenesis of subcutaneous WAT (scWAT). Depletion of iLNs in male mice results in defective cold-induced beiging of scWAT. Mechanistically, cold-enhanced sympathetic outflow to iLNs activates β1- and β2-adrenergic receptor (AR) signaling in FRCs to facilitate IL-33 release into iLN-surrounding scWAT, where IL-33 activates type 2 immune response to potentiate biogenesis of beige adipocytes. Cold-induced beiging of scWAT is abrogated by selective ablation of IL-33 or β1- and β2-AR in FRCs, or sympathetic denervation of iLNs, whereas replenishment of IL-33 reverses the impaired cold-induced beiging in iLN-deficient mice. Taken together, our study uncovers an unexpected role of FRCs in iLNs in mediating neuro-immune interaction to maintain energy homeostasis.

Natural killer (NK) cells are innate lymphocytes that play a key role in the control of infection and malignancy. NK cells are potent killers of target cells and act in an MHC-independent manner, enabling their application as allogenic therapy for cancer. Human iPSCs are pluripotent with the ability to self-renew, thus providing an inexhaustible source for deriving NK cells. With a two-tiered cell bank system, we can manufacture NK cells with more homogeneity between batches. In principle, one single iPSC clone-derived master cell bank and working cell banks can support the life cycle of an affordable, off-the-shelf NK cell product. We developed a robust stepwise protocol for large-scale generation of high-purity NK cells from human iPSCs without the cell isolation procedure. First, human iPSCs formed embryoid bodies and then were differentiated into highly purified (>98.0%) CD34 + CD43 + hematopoietic stem and progenitor cells (HSPCs) using a combination of cytokines and small molecles such as BMP-4, VEGF, BFGF, SCF, FLT-3 and ascorbic acid. During this period, we observed up to an 180-fold cell increase in the number of HSPCs compared with human iPSCs. Second, these HSPCs were differentiated into NK cells with FLT3, SCF, IL-3, IL-7, and IL-15 etc., with cell number increased approximately 9000-fold compared with iPSCs. In the final step, iPSC-derived NK cells were further expanded up to 8000-fold which enable us to produce 1E12 NK cells from less than 1 million iPSCs. After expansion, iNK cells became more homogenous and exhibited a more mature phenotype. More than 99.0% of cells expressed both CD45 and CD56, and more than 70% expressed CD16. The expression of activating and co-stimulatory receptors (NKG2D, NKp46,NKp44, NKp30, CD244 and CD226) of NK cells was also high in these iNK cells. Intrestingly, the cells exhibited robust anti-tumor efficacy against K562 (chronic myelogenous leukemia), RPMI 8226 (multiple myeloma). Furthermore, the cryopreserved iNK cells demonstrated dramatic cytotoxicity to U-87 MG cells (malignant gliomas) in 2D culture and the tumor organoid, indicating that iNK cells derived from our protocol can be used as off-the-shelf therapy for both hematological and solid tumors. We also observed that these iNK cells had variable cytotoxicity in other tumors. For example, our iNK were not obviously cytotoxic to the NCI-H929 cell line, derived from a plasmacytoma myeloma patient and expressing BCMA at a high level. To improve the specific cytotoxicity of NK cells to NCI-H929 cells, we transduced a anti-BCMA CAR to the donor iPSC. Following differentiation, the CAR-transduced iNK cells showed approximately 6-fold cytotoxicity compared with WT iNK. (Figure 1) Collectively, our serum-free and strom cell-free NK cell generation produre from human iPSCs provides a scalable, consistent, off-the-shelf and cost-effective NK/CAR-NK cell manufacturing platform for clinical application and NK cell-based immunotherapies.

Multiple myeloma (MM) is a hematological malignancy which characterized by malignant plasma cells resident in the bone marrow (BM). The BM microenvironment plays critical roles in the invasion, proliferation and migration of myeloma cells. Despite the therapies of MM improved in recent years, this disease is still incurable and requires precise treatment. Resident memory (TRM) cells are a distinct tissue-localized T cell lineage that is crucial for protective immunity in peripheral tissues. Recent studies reveal TRM cells as a vital component of the host immune response to cancer. TRM-like tumor-infiltrating lymphocytes (TILs) can be found in a wide range of human cancers, where they portend improved prognosis. However, the precise role and mechanism of bone marrow TRM cells in MM still remain elusive. In present study we first found that the accumulation of T RM cells (CD8 +CD44 +CD69 +CD62L -) in BM newly diagnosed MM (NDMM) patients was significantly higher than that of relapse recurrent MM (RRMM) ( Figure A), which was further confirmed by the immunohistochemistry (IHC) staining analysis ( Figure B). By using Seahorse XF e analyzer we found a decrease of oxygen consumption rate (OCR) of T RM cells in RRMM comparing to that of NDMM ( Figure C). Since fatty acid metabolism is important in β oxidation, we further investigated the expression of fatty acid binding proteins (FABP4/FABP5) in T RM cells and showed that FABP4 was dominant in T RM cells of NDMM patients ( Figure D). FABP4 +/+ mice and their relative controls FABP4 -/- mice were adopted to further explore the role and mechanism of T RM cells in MM progression. The abundance of genes related fatty acids β oxidation was significantly decreased in FABP4 -/- T RM cells ( Figure E). The tumor cell viability was decreased in myeloma cells co-cultured with FABP4 -/- T RM cells in the presence of bortezomib ( Figure F). Moreover, the expression of cytotoxic cytokines including IFN γ, TNFα and CXCL10 was significantly higher in FABP4 -/- T RM cells ( Figure G). The alarming function of T RM cells was further enhanced via recruiting more effector T (CD8 +CXCR3 +) cells ( Figure H), therefore the apoptosis of tumor cells was elevated in BM of MM patients. In summary, T RM cells are necessary and sufficient for long-lived protection against tumors. T RM cells derived FABP4 exerts anti-tumor immunity through prolonging the survival of T RM cells and enhancing the recruitment of more effector T cells to suppress the tumor progression ( Figure I). This study suggests that T RM cells might serve as a novel therapeutic target in MM and treatment specific targeting FABP4 might shed light on the development of potential therapeutic strategies for treating MM especially relapse patients. Acknowledgement This project is supported by the Sun Yat-sen University Hundred Talents Program (PT19200101), Natural Science Foundation of Guangdong Province (2022A1515010290).

Myeloma cells resident in bone marrow (BM), therefore the microenvironment plays critical roles in the invasion, proliferation and migration. Obesity increases the morbidity and drug resistance in patient of multiple myeloma (MM) through changing the bone marrow environment. Extracellular environments such as the BM plasma likely have unique lipidomic metabolite profiles that predicts the prognosis in patients with multiple myeloma. However, the study of multiple omics on metabolic changes in BM of MM patients are still very limited. The present study utilized an untargeted metabolite and targeted complex lipid profiling (Liquid chromatography-mass spectrometry, LC-MS) analysis to identify significant differences in the metabolite levels of BM plasma between newly diagnosed MM patients with different BMI (≤24 kg/m 2, n = 10; ≥25 kg/m 2, n = 10). This was followed by verification of some of the metabolite differences of interest by targeted quantification of the metabolites using isotopic internal standards in the exploratory cohort as well as an independent validation cohort. Significant differences were noted in the amino acid profiles, lipid metabolism and amino sugar metabolism, such as increased L-Glutamate, L-Proline, D-Proline, palmitoleic acid and D-Fructose, etc between MM patients with different BMI ( Figure A-C). Glycerol phosphate shuttle, glycerolipid metabolism and de novo triacylglycerol biosynthesis were the top 3 enriched signaling pathways in BM of obese MM patients ( Figure D). Targeted complex lipid profiling analysis further showed that triglyceride (TG)，diglyceride (DG) were increased notably in obese BM plasma of MM patients and correlated significantly with BMI ( Figure E-G). Glycerolipids, triradylglycerols, diradylglycerols and fatty acyls metabolism were enriched in obese group by GSEA analysis ( Figure H). Furthermore, KEGG enrichment analysis showed differentiate expressed lipid metabolites in BM plasma of obese MM patients comparing to that of lean group, including regulation of lipolysis in adipocytes, glycerolipid metabolism, fat digestion and absorption, cholesterol metabolism and metabolic pathways, etc ( Figure I ). In summary, metabolite and complex lipid profiling of the BM plasma identifies differences in levels of metabolites and lipids between MM patients with different BMI. This may provide insight into the explanation that obesity increases the susceptibility to MM and drug resistance. Acknowledgement This project is supported by the Sun Yat-sen University Hundred Talents Program (PT19200101), Natural Science Foundation of Guangdong Province (2022A1515010290).

Internal tandem duplication of FMS-like tyrosine kinase 3(FLT3-ITD)is one of the most common genetic alterations in human acute myeloid leukemia(AML)and confers a poor prognosis for the disease.1 Though several FLT3 inhibitors have been approved in AML,their clinical benefits are still unsatisfactory due to primary refractory and drug resis-tance.Therefore,it may be crucial to develop novel ther-apeutics for FLT3-ITD+AML.

Background: Exercise is an effective nonpharmacological strategy to alleviate diabetic cardiomyopathy (DCM) through poorly defined mechanisms. FGF21 (fibroblast growth factor 21), a peptide hormone with pleiotropic benefits on cardiometabolic homeostasis, has been identified as an exercise responsive factor. This study aims to investigate whether FGF21 signaling mediates the benefits of exercise on DCM, and if so, to elucidate the underlying mechanisms. Methods: The global or hepatocyte-specific FGF21 knockout mice, cardiomyocyte-selective β-klotho (the obligatory co-receptor for FGF21) knockout mice, and their wild-type littermates were subjected to high-fat diet feeding and injection of streptozotocin to induce DCM, followed by a 6-week exercise intervention and assessment of cardiac functions. Cardiac mitochondrial structure and function were assessed by electron microscopy, enzymatic assays, and measurements of fatty acid oxidation and ATP production. Human induced pluripotent stem cell–derived cardiomyocytes were used to investigate the receptor and postreceptor signaling pathways conferring the protective effects of FGF21 against toxic lipids-induced mitochondrial dysfunction. Results: Treadmill exercise markedly induced cardiac expression of β-klotho and significantly attenuated diabetes-induced cardiac dysfunction in wild-type mice, accompanied by reduced mitochondrial damage and increased activities of mitochondrial enzymes in hearts. However, such cardioprotective benefits of exercise were largely abrogated in mice with global or hepatocyte-selective ablation of FGF21, or cardiomyocyte-specific deletion of β-klotho. Mechanistically, exercise enhanced the cardiac actions of FGF21 to induce the expression of the mitochondrial deacetylase SIRT3 by AMPK-evoked phosphorylation of FOXO3, thereby reversing diabetes-induced hyperacetylation and functional impairments of a cluster of mitochondrial enzymes. FGF21 prevented toxic lipids-induced mitochondrial dysfunction and oxidative stress by induction of the AMPK/FOXO3/SIRT3 signaling axis in human induced pluripotent stem cell–derived cardiomyocytes. Adeno-associated virus-mediated restoration of cardiac SIRT3 expression was sufficient to restore the responsiveness of diabetic FGF21 knockout mice to exercise in amelioration of mitochondrial dysfunction and DCM. Conclusions: The FGF21-SIRT3 axis mediates the protective effects of exercise against DCM by preserving mitochondrial integrity and represents a potential therapeutic target for DCM. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03240978.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Coronavirus disease 2019 (COVID-19), which is known to be caused by the virus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is characterized by pneumonia, cytokine storms, and lymphopenia. Patients with malignant tumors may be particularly vulnerable to SARS-CoV-2 infection and possibly more susceptible to severe complications due to immunosuppression. Recent studies have found that CD209 (DC-SIGN) might be a potential binding receptor for SARS-CoV-2 in addition to the well-known receptor ACE2. However, pan-cancer studies of CD209 remain unclear. In this study, we first comprehensively investigated the expression profiles of CD209 in malignancies in both pan-carcinomas and healthy tissues based on bioinformatic techniques. The CD209 expression declined dramatically in various cancer types infected by SARS-CoV-2. Remarkably, CD209 was linked with diverse immune checkpoint genes and infiltrating immune cells. These findings indicate that the elevation of CD209 among specific cancer patients may delineate a mechanism accounting for a higher vulnerability to infection by SARS-CoV-2, as well as giving rise to cytokine storms. Taken together, CD209 plays critical roles in both immunology and metabolism in various cancer types. Pharmacological inhibition of CD209 antigen (D-mannose), together with other anti-SARS-CoV-2 strategies, might provide beneficial therapeutic effects in specific cancer patients.

Angiogenesis is essentially required for rapid tumor growth. In multiple myeloma (MM), bone marrow angiogenesis is considered as a hallmark for tumor progression. Increased microvessel density (MVD) is predictive of adverse outcome. However, cellular and molecular mechanism beyond MM angiogenesis remains ambiguous and requires further investigation. The present study aims to investigate the precise mechanism of bone marrow angiogenesis in MM and new potential therapeutic strategies targeting bone marrow microenvironment. We first analyzed public data of MM patients from TCGA database and found that CD320, a type I membrane protein sharing significant homology to low density lipoprotein receptor (LDL-R), was expressed abundantly in MM patients (Figure A). Next, newly diagnosed MM patients in our cancer center were recruited. Our data confirmed the high expression of CD320 in bone marrow of MM patients, which was responsible for increased MVD in MM bone marrow (Figure B) as well as enhanced angiogenic capacity of MM endothelial cells (MMECs) (Figure C). Moreover, high CD320 expression was correlated with poor prognosis in MM patients during the first 4 years (Figure D). Bioinformatics analysis (Figure E) and mechanistic investigations revealed that CD320 induced hepatocyte growth factor (HGF) expression through STAT signaling pathway (Figure F). Additionally, increased HGF level activates ERK1/2 pathway in endothelial cells and eventually resulted in enhanced angiogenesis. Conversely, enforced down-regulation of CD320 or HGF blunted this paracrine signaling pathway and angiogenic process (Figure G). Together, our results identify CD320 as a pivotal regulator in MM angiogenesis through HGF/ERK signaling pathway (Figure H). In conclusion, paracrine signaling by malignant plasma cells can induce bone marrow angiogenesis and results in increased migration and invasion characteristics of myeloma cells. These results suggested that targeting CD320 may act as a regulator of MM angiogenesis, thus representing a potential therapeutic strategy to prevent MM disease progression. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal