Discovery of N-Aryl-N′-[4-(aryloxy)cyclohexyl]squaramide-Based Inhibitors of LXR/SREBP-1c Signaling Pathway Ameliorating Steatotic Liver Disease: Navigating the Role of SIRT6 Activation

Article

作者: Jang, Eun Seo ; Kwak, Jinsook ; Jo, Jeyun ; Kwon, Oh-Bin ; Lee, Seoung Rak ; Hwang, Seonghwan ; Yun, Hwayoung ; Kim, Soyeong ; Kim, Sangok ; Kim, Sang-Bum ; Kim, Yeonsoo ; Song, Naghyun ; Son, Kyuwon ; Nguyen, Long Huu ; Kim, Tae-Jin ; Kim, Sanghyun ; Suh, Jung-Soo ; Choi, BuChul ; Hwang, Taeyeon ; Cho, Ye Eun ; Tak, Yealin ; Lee, Haeseung ; Lee, Jinyoung ; Kim, Minseong ; Kim, Jiah ; Lee, Eun-Woo

Metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily attributed to the abnormal upregulation of hepatic lipogenesis, which is especially caused by the overactivation of the liver X receptor/sterol regulatory element-binding protein-1c (LXR/SREBP-1c) pathway in hepatocytes. In this study, we report the rational design and synthesis of a novel series of squaramides via bioisosteric replacement, which was evaluated for its inhibitory activity on the LXR/SREBP-1c pathway using dual cell-based assays. Compound 31 was found to significantly downregulate LXR, SREBP-1c, and their target genes associated with lipogenesis. Further investigation revealed that compound 31 may indirectly inhibit the LXR/SREBP-1c pathway by activating the upstream regulator sirtuin 6 (SIRT6). Encouragingly, compound 31 substantially attenuated lipid accumulation in HepG2 cells and in the liver of high-fat-diet-fed mice. These findings suggest that compound 31 holds promise as a candidate for the development of treatments for MASLD and other lipid metabolism-related diseases.

2024-02-01·Advanced Science

BHLHE40 Inhibits Ferroptosis in Pancreatic Cancer Cells via Upregulating SREBF1

Article

作者: Zhang, Ronghao ; Tang, Xiaomei ; Luo, Jiaxin ; Wen, Chenlei ; Qin, Jiejie ; Liu, Jia ; Zhu, Youwei ; Liu, Pengyi ; Zhai, Shuyu ; Wang, Weishen ; Xue, Meilin ; Liu, Yihao ; Cao, Yizhi ; Jiang, Yongsheng ; Liu, Yang ; Han, Lijie ; Wang, Xuelong ; Wang, Liwen ; Shi, Minmin ; Cheng, Dongfeng ; Deng, Xiaxing ; Chen, Hao ; Jiang, Lingxi ; Shen, Baiyong ; Peng, Chenghong

AbstractPancreatic cancer (PCa) is one of the most fatal human malignancies. The enhanced infiltration of stromal tissue into the PCa tumor microenvironment limits the identification of key tumor‐specific transcription factors and epigenomic abnormalities in malignant epithelial cells. Integrated transcriptome and epigenetic multiomics analyses of the paired PCa organoids indicate that the basic helix‐loop‐helix transcription factor 40 (BHLHE40) is significantly upregulated in tumor samples. Increased chromatin accessibility at the promoter region and enhanced mTOR pathway activity contribute to the elevated expression of BHLHE40. Integrated analysis of chromatin immunoprecipitation‐seq, RNA‐seq, and high‐throughput chromosome conformation capture data, together with chromosome conformation capture assays, indicate that BHLHE40 not only regulates sterol regulatory element‐binding factor 1 (SREBF1) transcription as a classic transcription factor but also links the enhancer and promoter regions of SREBF1. It is found that the BHLHE40‐SREBF1‐stearoyl‐CoA desaturase axis protects PCa cells from ferroptosis, resulting in the reduced accumulation of lipid peroxidation. Moreover, fatostatin, an SREBF1 inhibitor, significantly suppresses the growth of PCa tumors with high expressions of BHLHE40. This study highlights the important roles of BHLHE40‐mediated lipid peroxidation in inducing ferroptosis in PCa cells and provides a novel mechanism underlying SREBF1 overexpression in PCa.

2023-07-01·Advanced Science

DEX‐Induced SREBF1 Promotes BMSCs Differentiation into Adipocytes to Attract and Protect Residual T‐Cell Acute Lymphoblastic Leukemia Cells After Chemotherapy (Adv. Sci. 19/2023)

作者: Ji, Chunyan ; Zhou, Ying ; Jia, Ruinan ; Li, Guosheng ; Xia, Yuan ; Sun, Tao ; Zhao, Xin ; Ye, Jingjing ; Li, Wei ; Ma, Daoxin ; Ji, Min

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant blood disorder with a high rate of relapse.Patients relapse as a result of minimal residual disease (MRD), which originates from residual T-ALL cells in the bone marrow microenvironment (BMM).In the present study, it is observed that adipocytes increase dramatically in the BMM of T-ALL patients after exposure to chemotherapeutic drugs.Then, it is proved that adipocytes attract T-ALL cells by releasing CXCL13 and support leukemia cell survival by activating the Notch1 signaling pathway via DLL1 and Notch1 binding.Furthermore, it is verified that dexamethasone (DEX) induces adipogenic differentiation by enhancing the expression of SREBF1 in bone marrow mesenchymal stromal cells (BMSCs), and an SREBF1 inhibitor significantly decreases the adipogenic potential of BMSCs and the subsequent ability of adipocytes to support T-ALL cells in vitro and in vivo.These findings confirm that the differentiation of BMSCs to adipocytes induced by DEX contributes to MRD in T-ALL and provides an auxiliary clin. treatment to reduce the recurrence rate.

100 项与 SREBF1 inhibitors(Pusan National University) 相关的药物交易

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