The oncogene DEK is found fused with the NUP214 gene creating oncoprotein DEK-NUP214 that induces acute myeloid leukemia (AML) in patients, and secreted DEK protein functions as a hematopoietic cytokine to regulate hematopoiesis; however, the intrinsic role of nuclear DEK in hematopoietic stem cells (HSCs) remains largely unknown. Here, we show that HSCs lacking DEK display defects in long-term self-renew capacity, eventually resulting in impaired hematopoiesis. DEK deficiency reduces quiescence and accelerates mitochondrial metabolism in HSCs, in part, dependent upon activating mTOR signaling. At the molecular level, DEK recruits the corepressor NCoR1 to repress acetylation of histone 3 at lysine 27 (H3K27ac) and restricts the chromatin accessibility of HSCs, governing the expression of quiescence-associated genes (e.g., Akt1/2, Ccnb2, and p21). Inhibition of mTOR activity largely restores the maintenance and potential of Dek-cKO HSCs. These findings highlight the crucial role of nuclear DEK in preserving HSC potential, uncovering a new link between chromatin remodelers and HSC homeostasis, and have clinical implications.

The activation of hepatic stellate cells (HSCs) has proved to be pivotal in hepatic fibrosis. Therefore, the suppression of HSC activation is an effective anti-fibrotic strategy. Although studies have indicated that eupatilin, a bioactive flavone found in Artemisia argyi, has anti-fibrotic properties, the effect of eupatilin on hepatic fibrosis is currently unclear. In this study, we used the human hepatic stellate cell line LX-2 and the classical CCl4-induced hepatic fibrosis mouse model for in vitro and vivo experiments. We found that eupatilin significantly repressed the levels of the fibrotic markers COL1α1 and α-SMA, as well as other collagens in LX-2 cells. Meanwhile, eupatilin markedly inhibited LX-2 cell proliferation, as verified by the reduced cell viability and down-regulation of c-Myc, cyclinB1, cyclinD1, and CDK6. Additionally, eupatilin decreased the level of PAI-1 in a dose-dependent manner, and knockdown of PAI-1 using PAI-1-specific shRNA significantly suppressed the levels of COL1α1, α-SMA, and the epithelial–mesenchymal transition (EMT) marker N-cadherin in LX-2 cells. Western blotting indicated that eupatilin reduced the protein level of β-catenin and its nuclear translocation, while the transcript level of β-catenin was not affected in LX-2 cells. Furthermore, analysis of histopathological changes in the liver and markers of liver function and fibrosis revealed that hepatic fibrosis in CCl4-treated mice was markedly alleviated by eupatilin. In conclusion, eupatilin ameliorates hepatic fibrosis and hepatic stellate cell activation by suppressing the β-catenin/PAI-1 pathway.

Scutellaria baicalensis Georgi, a traditional Chinese herb, is known for its various biological effects, including antibacterial, anti-inflammatory, antioxidative, and antitumor properties. However, the function and mechanisms of methanol extract of Scutellaria baicalensis Georgi (MESB) in treating hepatic fibrosis remain unclear. This study utilized a CCl4-induced mouse model of hepatic fibrosis to assess the effects of MESB through histopathological analysis and serum tests. The anti-fibrosis mechanism of MESB was investigated using qPCR, Western blotting, RNA interference, proteomics, and metabolomics. Spatial metabolomics identified key components of MESB in liver tissue, while molecular docking determined their targets. Treatment with MESB alleviated hepatic pathological changes and reversed hepatic fibrosis in the CCl4-induced models, as evidenced by decreased collagen fibers deposition, reduced expression of hepatic fibrosis markers COL1A1, FN, and PAI-1, and lowered serum levels of AST and ALT. In vitro, MESB inhibited the proliferation of LX-2 cells and the expression of hepatic fibrosis markers. Furthermore, MESB intervention modulated various pathways, particularly those involved in metabolic pathways. Subsequent metabolomics analysis demonstrated that MESB disrupted glycerophospholipid metabolism and suppressed arachidonic acid metabolism. MESB downregulated the expression of cPLA2 in LX-2 cells, leading to decreased production of arachidonic acid and its downstream inflammatory mediators. Meanwhile, MESB inhibited the expression of cPLA2 and its downstream NF-κB pathway in the liver tissues of models induced by CCl4. Additionally, silencing cPLA2 markedly reduced the expressions of COL1A1, FN, and PAI-1. Spatial metabolomics analysis confirmed the penetration of baicalein, wogonin and wogonoside into liver tissue. Further results indicated that baicalein and wogonin inhibited the expression of cPLA2, while baicalin and wogonoside do not exhibit this effect. Moreover, molecular docking suggested that baicalein and wogonin possess the potential to directly interact with cPLA2. This study reveals that MESB is crucial in preventing hepatic fibrosis via the cPLA2-mediated arachidonic acid metabolic pathway, highlighting its key active components as potential drugs for fibrosis treatment.

Chronic kidney disease (CKD) is a major health concern, with renal interstitial fibrosis (RIF) as a key feature. Effective management of RIF is crucial for treating CKD. Yiqi Juanshen decoction (YQJSD), as traditional Chinese medicine, has shown promising results in CKD treatment. This study evaluates YQJSD’s effectiveness in ameliorating RIF and explores the underlying molecular mechanisms using the unilateral ureteral obstruction (UUO) model. YQJSD has been shown to effectively reduce serum creatinine and blood urea nitrogen levels, decrease extracellular matrix deposition, and down-regulate the expression of α-SMA, COL4α1, Fibronectin (FN). Mechanistically, YQJSD exerts its effects by modulating multiple pathways: it inhibits the NF-κB signaling pathway, inhibiting the expression of pro-inflammatory cytokines like NF-κB1, IL-1β, TNF-α, and CCR1. Simultaneously, YQJSD suppresses the epithelial-mesenchymal transition (EMT) by downregulating the expression of Snail1, Vimentin, Twist1, and FSP1, while increasing E-cadherin expression. Moreover, YQJSD can regulate the PI3K/AKT signaling pathway by decreasing the expression of LOXL2 and PIK3R1, along with p-AKT1/2/3. This modulation of the LOXL2/PI3K/AKT pathway contributes to the inhibition of both EMT and inflammation, highlighting a critical role in the therapeutic intervention against RIF. These findings suggest that YQJSD may serve as a promising therapeutic management of RIF in CKD patients.

Background: Hepatic fibrosis is a major global health issue without an optimal drug treatment, highlighting the urgent need to find effective therapies. This study aimed to clarify the role and mechanism of micheliolide in treating hepatic fibrosis. Methods: The efficacy of MCL was evaluated in a mouse model of CCl₄-induced hepatic fibrosis. LX-2 cells were subjected to MCL treatment, and subsequent changes in fibrosis markers, autophagy, and the MEK/ERK pathway were analyzed using transcriptomics and Western blotting. The interaction between MCL and TrxR1 or TrxR2 were validated using cellular thermal shift assays (CETSA) and drug affinity responsive target stability (DARTS) assays. Results: Our findings indicated that MCL significantly alleviated CCl₄-induced hepatic fibrosis, improved liver function, and downregulated the expression of fibrosis markers. Additionally, MCL significantly inhibited LX-2 cell activation by suppressing cell proliferation, extracellular matrix (ECM) production, and autophagy, while activating the MEK/ERK pathway. Moreover, MCL elevated intracellular and mitochondrial reactive oxygen species (ROS) levels, reduced mitochondrial membrane potential, and altered mitochondrial morphology. The ROS scavenger N-acetylcysteine (NAC) attenuated MCL-induced MEK/ERK pathway activation and increased collagen type I alpha 1 (COL1A1) and fibronectin (FN) expression. Further analysis confirmed that MCL directly interacts with TrxR1 and TrxR2, leading to the inhibition of their enzymatic activities and the induction of ROS generation. Ultimately, MCL attenuated the fibrotic process and autophagic flux in LX-2 cells. Conclusions: The findings of our study confirmed that MCL has the potential to alleviate hepatic fibrosis, thereby introducing a novel candidate drug and therapeutic strategy for management of this condition.