Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. STAM binding protein-like 1 (STAMBPL1), a key member of the COP9 signalosome subunit 5/serine protease 27/proteasome 26S subunit non-ATPase 7 (JAMM) family, is closely associated with tumor development. In this work, data from GSE101728 and GSE84402 chips were analyzed, and STAMBPL1 was selected as the target factor. This study aimed to reveal the potential function of STAMBPL1 in HCC. Clinical results showed that STAMBPL1 was significantly increased in tumor tissues of HCC patients, and its expression was strongly associated with tumor size and TNM stage. Furthermore, STAMBPL1-overexpressed Hep3B2.1-7 cell line or STAMBPL1-silenced SNU-182 cell line were established using lentivirus carrying cDNA encoding STAMBPL1 mRNA or shRNA targeting STAMBPL1, respectively. STAMBPL1-overexpressed cells exhibited a pronounced enhancement of proliferation in vitro and in vivo. Exogenous expression of STAMBPL1 increased the percentage of cells in the S phase and upregulated the expressions of CyclinD1 and Survivin. As expected, STAMBPL1 knockdown exhibited completely opposite effects, resulting in impaired tumorigenicity in vitro and in vivo. Mechanistically, STAMBPL1 activated Wnt/β-catenin pathway and increased the expression of downstream cancer-promoting genes. Interestingly, we found that STAMBPL1 was transcriptionally regulated by sterol regulatory element-binding protein 1 (SREBP1), a modulator of lipid metabolism, as evidenced by luciferase reporter and chromatin-immunoprecipitation (Ch-IP) assays. Notably, STAMBPL1 overexpression increased lipid accumulation in HCC cells and xenograft tumors. Totally our findings suggest that STAMBPL1 plays a vital role in the tumorigenicity of HCC cells. Modulation of Wnt/β-catenin and lipid metabolism may contribute to its pro-cancer effects. STAMBPL1 may serve as a therapeutic target of HCC.

Non-alcoholic fatty liver disease (NAFLD) constitutes one of major worldwide health problem which typically progressively results in non-alcoholic steatohepatitis (NASH) and eventually cirrhosis and liver cancer. Liver-specific deletion of INSIG1 promotes SREBP1 nuclear translocation to activate downstream lipogenic genes expression, leading to lipid accumulation. However, the underlying pathogenesis of NAFLD, and particularly involved in miRNA participation are still to be thoroughly explored. Here, we found that miR-363-3p was significantly overexpressed in high-fat, high-cholesterol (HFHC) diet mice liver tissue and fatty acid-induced steatosis cells. miR-363-3p directly targets INSIG1 to inhibit its expression, thereby facilitating the cleavage of SREBP and nuclear translocation to activate subsequent transcription of lipogenic genes in vitro and in vivo. In addition, we identified apigenin, a natural flavonoid compound, inhibited miR-363-3p expression to up-regulate INSIG1 and suppress nuclear translocation of SREBP1, thereby down-regulated lipogenic genes expression in steatosis cells and HFHC diet mice liver tissues. Taken together, our results demonstrated that miR-363-3p as a key regulator of hepatic lipid homeostasis targeted INSIG1, and apigenin alleviated NAFLD through the miR-363-3p/INSIG1/SREBP1 pathway. This indicates that reduction of miR-363-3p levels as a possible treatment of hepatic steatosis and provides a potential new therapeutic strategy for targeting miRNA to ameliorate NAFLD.

T-cell acute lymphoblastic leukaemia (T-ALL) is a highly aggressive and heterogeneous lymphoid malignancy with poor prognosis in adult patients. Aberrant activation of the NOTCH1 signalling pathway is involved in the pathogenesis of over 60% of T-ALL cases. Ubiquitin-specific protease 28 (USP28) is a deubiquitinase known to regulate the stability of NOTCH1. Here, we report that genetic depletion of USP28 or using CT1113, a potent small molecule targeting USP28, can strongly destabilize NOTCH1 and inhibit the growth of T-ALL cells. Moreover, we show that USP28 also regulates the stability of sterol regulatory element binding protein 1 (SREBP1), which has been reported to mediate increased lipogenesis in tumour cells. As the most critical transcription factor involved in regulating lipogenesis, SREBP1 plays an important role in the metabolism of T-ALL. Therefore, USP28 may be a potential therapeutic target, and CT1113 may be a promising novel drug for T-ALL with or without mutant NOTCH1.

Flavonoids exhibit health-promoting benefits against multiple chronic diseases, including cancer. Apigenin (4\',5,7-trihydroxyflavone), one flavonoid present in fruits and vegetables, is potentially applicable to chemoprevention. Despite considerable progress in the therapeutic regimen of liver cancer, its prognosis remains poor. MED28, a Mediator subunit for transcriptional activation, is implicated in the development of several types of malignancy; however, its role in liver cancer is unknown at present. In liver cancer, the AKT/mammalian target of rapamycin (mTOR) is one major pathway involved in the oncogenic process. The aim of this study is to investigate the role of apigenin and MED28 in AKT/mTOR signaling in liver cancer. We first identified a connectivity score of 92.77 between apigenin treatment and MED28 knockdown in several cancer cell lines using CLUE, a cloud-based software platform to assess connectivity among compounds and genetic perturbagens. Higher expression of MED28 predicted a poorer survival prognosis; MED28 expression in liver cancer tissue was significantly higher than that of normal tissue, and it was positively correlated with tumor stage and grade in The Cancer Genome Atlas Liver Cancer (TCGA-LIHC) data set. Knockdown of MED28 induced cell cycle arrest and suppressed the AKT/mTOR signaling in two human liver cancer cell lines, HepG2 and Huh 7, accompanied by less lipid accumulation and lower expression and nuclear localization of sterol regulatory element binding protein 1 (SREBP1). Apigenin inhibited the expression of MED28, and the effect of apigenin mimicked that of the MED28 knockdown. On the other hand, the AKT/mTOR signaling was upregulated when MED28 was overexpressed. These data indicated that MED28 was associated with the survival prognosis and the progression of liver cancer by regulating AKT/mTOR signaling and apigenin appeared to inhibit cell growth through MED28-mediated mTOR signaling, which may be applicable as an adjuvant of chemotherapy or chemoprevention in liver cancer.

Cancer occurrence and development are closely related to increased lipid production and glucose consumption. Lipids are the basic component of the cell membrane and play a significant role in cancer cell processes such as cell-to-cell recognition, signal transduction, and energy supply, which are vital for cancer cell rapid proliferation, invasion, and metastasis. Sterol regulatory element-binding transcription factor 1 (SREBP1) is a key transcription factor regulating the expression of genes related to cholesterol biosynthesis, lipid homeostasis, and fatty acid synthesis. In addition, SREBP1 and its upstream or downstream target genes are implicated in various metabolic diseases, particularly cancer. However, no review of SREBP1 in cancer biology has yet been published. Herein, we summarized the roles and mechanisms of SREBP1 biological processes in cancer cells, including SREBP1 modification, lipid metabolism and reprogramming, glucose and mitochondrial metabolism, immunity, and tumor microenvironment, epithelial-mesenchymal transition, cell cycle, apoptosis, and ferroptosis. Additionally, we discussed the potential role of SREBP1 in cancer prognosis, drug response such as drug sensitivity to chemotherapy and radiotherapy, and the potential drugs targeting SREBP1 and its corresponding pathway, elucidating the potential clinical application based on SREBP1 and its corresponding signal pathway.

BACKGROUND: Autophagy could sense metabolic conditions and safeguard cells against nutrient deprivation, ultimately supporting the survival of cancer cells. Nobiletin (NOB) is a kind of bioactive component of the traditional Chinese medicine Citri Reticulatae Pericarpium and has been proven to induce GC cell death by reducing de novo fatty acid synthesis in our previous study. Nevertheless, the precise mechanisms by which NOB induces cell death in GC cells still need further elucidation.
OBJECTIVE: To examine the mechanism by which NOB inhibits gastric cancer progression through the regulation of autophagy under the condition of lipid metabolism inhibition.
UNASSIGNED: Proliferation was detected by the CCK-8 assay. RNA sequencing (RNA-seq) was used to examine signaling pathway changes. Electron microscopy and mRFP-GFP-LC3 lentiviral transfection were performed to observe autophagy in vitro. Western blot, plasmid transfection, immunofluorescence staining, and CUT & Tag-qPCR techniques were utilized to explore the mechanisms by which NOB affects GC cells. Molecular docking and molecular dynamics simulations were conducted to predict the binding mode of NOB and SREBP1. CETSA was adopted to verify the predicted of binding model. A patient-derived xenograft (PDX) model was employed to verify the therapeutic efficacy of NOB in vivo.
RESULTS: We conducted functional studies and discovered that NOB inhibited the protective effect of autophagy via the PI3K/Akt/mTOR axis in GC cells. Based on previous research, we found that the overexpression of ACLY abrogated the NOB-induced autophagy-dependent cell death. In silico analysis predicted the formation of a stable complex between NOB and SREBP1. In vitro assays confirmed that NOB treatment increased the thermal stability of SREBP1 at the same temperature conditions. Moreover, CUT&TAG-qPCR analysis revealed that NOB could inhibit SREBP1 binding to the ACLY promoter. In the PDX model, NOB suppressed tumor growth, causing SREBP1 nuclear translocation inhibition, PI3K/Akt/mTOR inactivation, and autophagy-dependent cell death.
CONCLUSIONS: NOB demonstrated the ability to directly bind to SREBP1, inhibiting its nuclear translocation and binding to the ACLY promoter, thereby inducing autophagy-dependent cell death via PI3K/Akt/mTOR pathway.

Metabolic reprogramming is a hallmark of cancer. The nicotinamide phosphoribosyltransferase (NAMPT)-mediated salvage pathway maintains sufficient cellular NAD levels and is required for tumorigenesis and development. However, the molecular mechanism by which NAMPT contributes to HBV-associated hepatocellular carcinoma (HCC) remains not fully understood. In the present study, our results showed that NAMPT protein was obviously upregulated in HBV-positive HCC tissues compared with HBV-negative HCC tissues. NAMPT was positively associated with aggressive HCC phenotypes and poor prognosis in HBV-positive HCC patients. NAMPT overexpression strengthened the proliferative, migratory, and invasive capacities of HBV-associated HCC cells, while NAMPT-insufficient HCC cells exhibited decreased growth and mobility. Mechanistically, we demonstrated that NAMPT activated SREBP1 (sterol regulatory element-binding protein 1) by increasing the expression and nuclear translocation of SREBP1, leading to the transcription of SREBP1 downstream lipogenesis-related genes and the production of intracellular lipids and cholesterol. Altogether, our data uncovered an important molecular mechanism by which NAMPT promoted HBV-induced HCC progression through the activation of SREBP1-triggered lipid metabolism reprogramming and suggested NAMPT as a promising prognostic biomarker and therapeutic target for HBV-associated HCC patients.

Status epilepticus (SE) is a life-threatening disorder that can result in death or severe brain damage, and there is a substantial body of evidence suggesting a strong association between pyroptosis and SE. Sterol regulatory element binding protein 1 (SREBP1) is a significant transcription factor participating in both lipid homeostasis and glucose metabolism. However, the function of SREBP1 in pyroptosis during SE remains unknown. In this study, we established a SE rat model by intraperitoneal injection of lithium chloride and pilocarpine in vivo. Additionally, we treated HT22 hippocampal cells with glutamate to create neuronal injury models in vitro. Our results demonstrated a significant induction of SREBP1, inflammasomes, and pyroptosis in the hippocampus of SE rats and glutamate-treated HT22 cells. Moreover, we found that SREBP1 is regulated by the mTOR signaling pathway, and inhibiting mTOR signaling contributed to the amelioration of SE-induced hippocampal neuron pyroptosis, accompanied by a reduction in SREBP1 expression. Furthermore, we conducted siRNA-mediated knockdown of SREBP1 in HT22 cells and observed a significant reversal of glutamate-induced cell death, activation of inflammasomes, and pyroptosis. Importantly, our confocal immunofluorescence analysis revealed the co-localization of SREBP1 and NLRP1. In conclusion, our findings suggest that deficiency of SREBP1 attenuates glutamate-induced HT22 cell injury and hippocampal neuronal pyroptosis in rats following SE. Targeting SREBP1 may hold promise as a therapeutic strategy for SE.

UNASSIGNED: To investigate the role and mechanism of trimethylamine N-oxide (TMAO), a uremic toxin, in renal fibrosis.
UNASSIGNED: A total of 20 male BALB/c mice were randomly and evenly assigned to a Control group and a TMAO group. Mice in the Control group received intraperitoneal injection of normal saline, while mice in the TMAO group received intraperitoneal injection of TMAO (20 mg/[kg·d]). The injection was given once a day for 8 weeks. Histopathology and fibrosis of kidney were observed by H&E staining and Masson staining. Immunohistochemistry was performed to determine the levels of alpha smooth muscle actin (α-SMA), recombinant human fibronectin fragment (Fibronectin), and sterol-regulatory element binding protein 1 (SREBP1). Western blot was performed to determine α-SMA, SREBP1, phosphatidylinositol 3 kinase (PI3K), phospho-phosphatidylinositol 3 kinase (p-PI3K), protein kinase B (PKB, also known as AKT), and phospho-AKT (p-AKT) protein levels. HK2 cells were treated with SREBP1 small interfering RNA (siRNA) and PI3K/AKT inhibitor, respectively, and the reversal of the effects of TMAO was examined.
UNASSIGNED: Animal experiments showed that, compared with the Control group, the mice treated with TMAO experienced pathological damage and fibrosis of the kidney tissue and the expression levels of fibrosis markers, α-SMA and Fibronectin, in the kidney were increased (all P<0.05). According to the findings from further investigation, the TMAO-treatment group showed increased expression of SREBP1 and an up-regulation of PI3K phosphorylation ratio and AKT phosphorylation ratio compared with those of the Control group (all P<0.05). Cell experiments produced results similar to those of the animal experiment. After siRNA interference with SREBP1 expression, the expression levels of fibrosis marker proteins decreased (P<0.05). Besides, the high expression of SREBP1 caused by TMAO was inhibited after HK2 cells were incubated with LY294002, a PI3K-AKT pathway inhibitor (P<0.05).
UNASSIGNED: TMAO may induce renal fibrosis by promoting the PI3K/AKT/SREBP1 pathway.

BACKGROUND: Cinobufacini injection, an aqueous extract of the toad, is a commonly used anti-tumor animal herbal medicine in clinical practice. It has the effects of detoxifying, reducing swelling, and relieving pain.
OBJECTIVE: To investigate the effects of Cinobufacini injection on hepatocellular carcinoma progression by regulating lipid metabolism and macrophage polarization in the tumor microenvironment and to identify the potential molecular mechanisms.
METHODS: To establish the axillary transplantation tumor model of hepatocellular carcinoma Hepa1-6 in C57BL/6 mice, and to evaluate the inhibitory effect of Cinobufacini injection on hepatocellular carcinoma in vivo as well as drug delivery security. Combined metabolomics and transcriptomics analysis of the effect of Cinobufagin Injection on tumor microenvironment. An in vitro mouse co-culture model of peritoneal macrophages and Hepa1-6 cells was established to research the effects of Cinobufacini injection on macrophage polarization, hepatocellular carcinoma cell growth, migration, and changes in lipid metabolism. Cinobufacini injection inhibition of the AMPK/SREBP1/FASN signaling pathway regulating cholesterol metabolism and affecting macrophage polarization was examined using qRT-PCR, lentiviral transfection, immunofluorescence, and Western blot.
RESULTS: In vivo experiments demonstrated that Cinobufacini injection treatment significantly inhibited the growth of Hepa1-6 hepatomas, along with a reduction in cholesterol content and a decrease in the percentage of M2 macrophages in tumor tissue. In vitro, we found that Cinobufacini injection inhibits IL-4-induced M2 macrophage polarization, reduces the cholesterol content of Hepa1-6 cells in a co-culture system, and inhibits the promotion of hepatocellular carcinoma cells by M2 macrophages. In addition, successful overexpression of SREBP1 in Hepa1-6 cells showed more pronounced cellular activity whereas Cinobufacini injection inhibited this change and reduced intracellular lipid levels.
CONCLUSIONS: Cinobufacini injection inhibits cholesterol synthesis within the tumor microenvironment via the AMPK/SERBP1/FASN signaling pathway, which in turn blocks the M2 polarization of macrophages, leading to the weakening of hepatocellular carcinoma growth and migration, and the promotion of its apoptosis. Our findings provide an important Introduction to understanding the molecular mechanism of Cinobufacini injection\'s anticancer activity and provide reliable theoretical and experimental support for its clinical application.