Wenquan Hu

Glucose transporter-1 is known for regulating glucose uptake in brain endothelial cells. This study used global transcriptome analysis and diabetic mouse models to reveal the novel role of glucose transporter 1 in regulating brain endothelial cell homeostasis by reducing the inflammation response and increasing the protection mechanism. Importantly, the glucose transporter 1-dependent protection mechanism is compromised in diabetic conditions, which explains why patients with diabetes have a high risk of cerebrovascular diseases.

Acetate is the end product of alcohol metabolism. Acyl-CoA synthetase short-chain family member 2 (ACSS2) converts acetate to acetyl-CoA, involving metabolic pathways and epigenetic regulation. However, the function of ACSS2-mediated epigenetic control in alcoholic liver disease (ALD) remains incompletely understood. We demonstrate that alcohol downregulates hepatic ACSS2, causing acetate accumulation in the liver and serum. This disrupts iron metabolism and hepatic ferroptosis, triggering liver injury and inflammation. Mechanistically, ACSS2 binds CREB binding protein (CBP) to mediate histone acetylation and regulate hepcidin antimicrobial peptide 1/2 (HAMP1/2) transcription. ACSS2 deficiency downregulates HAMP1/2, causing systemic iron dyshomeostasis and ferroptosis, which is restored by overexpression of HAMP1/2. Iron chelators or ferroptosis inhibitors attenuates alcohol-induced liver injury in ACSS2-deficient mice. Our study uncovers the epigenetic mechanisms of ACSS2-mediated ferroptosis and its role in ALD progression.

Purpose Non-small cell lung cancer (NSCLC) is a subtype of the most frequently diagnosed cancer, causing a considerable number of deaths globally. Mitochondrial dysfunction has been observed to promote malignant progression. However, the underlying mechanism is still unclear. Acyl-CoA synthetase short chain family member 3 (ACSS3) is mainly located in mitochondria, which abnormal regulation is usually accompanied by the occurrence and development of tumors. This study aimed to evaluate the potential role of ACSS3 in the tumorigenesis of NSCLC. Methods The impact of ACSS1 and ACSS3 expression levels on the survival rates of NSCLC patients was examined by online database. ACSS3 protein expression in 79 NSCLC samples and 79 adjacent tissues was evaluated by immunohistochemistry (IHC). The effect of ACSS3 on proliferation, migration and invasion of NSCLC and the molecular mechanism were investigated through in vitro experiments and xenograft tumor. Results ACSS3 expression level was correlated with the poor prognosis of NSCLC patients. ACSS3 knockdown led to mitochondrial contraction, increased ROS levels, decreased mitochondrial membrane potential, and subsequently inhibited growth of NSCLC cells in vitro and in vivo, while ACSS3 overexpression promoted these processes. Mechanistically, ACSS3 deficiency promoted ferroptosis through transcriptional control of SLC7A11 and GPX4. Further investigations found that loss of ACSS3 inhibited the SLC7A11/GPX4 axis by enhancing the stability of p53. Conclusion ACSS3 promotes NSCLC tumorigenesis through inhibiting the p53-mediated ferroptosis. As such, ACSS3 should be considered a new potential therapeutic target for the treatment of NSCLC.

The loss function of cerebral cavernous malformation (CCM) genes leads to most CCM lesions characterized by enlarged leaking vascular lesions in the brain. Although we previously showed that NOGOB receptor (NGBR) knockout in endothelial cells (ECs) results in cerebrovascular lesions in the mouse embryo, the molecular mechanism by which NGBR regulates CCM1/2 expression has not been elucidated. Here, we show that genetic depletion of Ngbr in ECs at both postnatal and adult stages results in CCM1/2 expression deficiency and cerebrovascular lesions such as enlarged vessels, blood-brain-barrier hyperpermeability, and cerebral hemorrhage. To reveal the molecular mechanism, we used RNA-sequencing analysis to examine changes in the transcriptome. Surprisingly, we found that the acetyltransferase HBO1 and histone acetylation were downregulated in NGBR-deficient ECs. The mechanistic studies elucidated that NGBR is required for maintaining the expression of CCM1/2 in ECs via HBO1-mediated histone acetylation. ChIP-qPCR data further demonstrated that loss of NGBR impairs the binding of HBO1 and acetylated histone H4K5 and H4K12 on the promotor of the CCM1 and CCM2 genes. Our findings on epigenetic regulation of CCM1 and CCM2 that is modulated by NGBR and HBO1-mediated histone H4 acetylation provide a perspective on the pathogenesis of sporadic CCMs.