Previous studies mainly focused on the role of the epidermal growth factor receptor (EGFR) in tumor cells, whereas the effects of the EGFR on immune responses has not been determined. Our study shows that the EGFR signaling pathway play a role in the regulation of regulatory T cells (Treg cells) in cancer patients. The EGF-like growth factor Amphiregulin (AREG) protein was frequently up-regulated in a tissue microarray, which was associated with worse overall survival. Additionally, in sera, tissue specimens, and effusions of lung or gastric cancer patients, up-regulated AREG protein enhanced the suppressive function of Treg cells. AREG maintained the Treg cell suppressive function via the EGFR/GSK-3β/Foxp3 axis in vitro and in vivo. Furthermore, inhibition of EGFR by the tyrosine kinase inhibitor gefitinib restored the activity of GSK-3β and attenuated Treg cell function. β-TrCP was involved in GSK-3β-mediated Foxp3 degradation, and mass spectrometry identified Lys³⁵⁶ as the ubiquitination site of Foxp3 by β-TrCP. These findings demonstrate the posttranslational regulation of Foxp3 expression by AREG in cancer patients through AREG/EGFR/GSK-3β signaling, which could lead to Foxp3 protein degradation in Treg cells and a potential therapeutic target for cancer treatment.

Nonalcoholic fatty liver disease (NAFLD), ranging from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH), is the leading cause of chronic liver diseases. Until now, no medications for NAFLD have been approved by relevant governmental agencies. Dual‐specificity phosphatase 9 (Dusp9) is a member of the DUSP protein family. Dusp9 is expressed in insulin‐sensitive tissues, and its expression may be modified with the development of insulin resistance (IR). However, the molecular targets and mechanisms of Dusp9 action on NAFLD and NASH remain poorly understood. In this study, using conditional liver‐specific Dusp9‐knockout (Dusp9‐CKO) mice and Dusp9‐transgenic mice, we showed that Dusp9 was a key suppressor of high‐fat diet–induced hepatic steatosis and inflammatory responses and that Dusp9 deficiency aggravated high‐fat high‐cholesterol diet–induced liver fibrosis. Dusp9 was shown to exert its effects by blocking apoptosis signal–regulating kinase 1 (ASK1) phosphorylation and the subsequent activation of p38 and c‐Jun NH2‐terminal kinase signaling. Conclusion: Hepatocyte Dusp9 prevents NAFLD and NASH progression in mice, including lipid accumulation, glucose metabolism disorders, and enhanced inflammation and liver fibrosis, in an ASK1‐dependent manner; these findings suggest that Dusp9 may be a promising therapeutic target for the treatment of NAFLD and NASH.

Objective—: Thoracic aortic aneurysm and dissection (TAAD) are severe vascular conditions. Dysfunctional transforming growth factor-β (TGF-β) signaling in vascular smooth muscle cells and elevated angiotensin II (AngII) levels are implicated in the development of TAAD. In this study, we investigated whether these 2 factors lead to TAAD in a mouse model and explored the possibility of using microRNA-21 ( miR-21 ) for the treatment of TAAD. Approach and Results—: TAAD was developed in Smad3 (mothers against decapentaplegic homolog 3) heterozygous (S3 ^+/− ) mice infused with AngII. We found that p-ERK (phosphorylated extracellular regulated protein kinases)– and p-JNK (phosphorylated c-Jun N-terminal kinase)–associated miR-21 was higher in TAAD lesions. We hypothesize that downregulation of miR-21 mitigate TAAD formation. However, Smad3 ^+/− :miR-21 ^−/− (S3 ^+/− 21 ^−/− ) mice exhibited conspicuous TAAD formation after AngII infusion. The vascular wall was dilated, and aortic rupture occurred within 23 days during AngII infusion. We then examined canonical and noncanonical TGF-β signaling and found that miR-21 knockout in S3 ^+/− mice increased SMAD7 and suppressed canonical TGF-β signaling. Vascular smooth muscle cells lacking TGF-β signals tended to switch from a contractile to a synthetic phenotype. The silencing of Smad7 with lentivirus prevented AngII-induced TAAD formation in S3 ^+/− 21 ^−/− mice. Conclusions—: Our study demonstrated that miR-21 knockout exacerbated AngII-induced TAAD formation in mice, which was associated with TGF-β signaling dysfunction. Therapeutic strategies targeting TAAD should consider unexpected side effects associated with alterations in TGF-β signaling.

Background: The development of thoracic aortic aneurysm and dissection (TAAD) is mediated by inflammasome activation, which exacerbates the secretion of pro-inflammatory cytokines, chemokines, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS). The glycolytic enzyme pyruvate kinase M2 (PKM2) has shown a protective role against various disorders with an inflammatory basis, such as sepsis, tumorigenesis, and diabetic nephropathy. However, its potential role in TAAD has not been investigated so far. Approach and Results: We analyzed aortic tissues from TAAD patients and the β-aminopropionitrile fumarate (BAPN)–induced mouse model of TAAD and observed elevated levels of PKM2 in the aortic lesions of both. Treatment with the PKM2 activator TEPP-46 markedly attenuated the progression of TAAD in the mouse model as demonstrated by decreased morbidity and luminal diameter of the aorta. In addition, the thoracic aortas of the BAPN-induced mice showed reduced monocytes and macrophages infiltration and lower levels of IL-1β, MMPs, and ROS when treated with TEPP-46. Furthermore, TEPP-46 treatment also suppressed the activation of the NOD-like receptor (NLR) family and pyrin domain–containing protein 3 (NLRP3) inflammasome by downregulating p-STAT3 and HIF1-α. Conclusion: Pyruvate kinase M2 plays a protective role in TAAD development, and its activation is a promising therapeutic strategy against the progression of TAAD.