Wenshuang Wu

DNA damage repair (DDR) is essential for cancer cell survival and treatment resistance, making it a critical target for tumor therapy. The eukaryotic AAA+ adenosine triphosphatase valosin-containing protein (VCP), which is transported from the cytoplasm into the nucleus, plays a critical role in the DDR process. However, the nuclear translocation and molecular mechanism of VCP for DDR remain elusive. Here, we define VCP as a KPNB1 interacting protein through a combination of chemical and immunoprecipitation mass spectrometry approaches. Further biochemical studies elucidate that KPNB1 directly transports VCP into the nucleus. We also identify withaferin A (WA) as a small molecule that can retard VCP nuclear localization via covalent binding to CYS 158 of KPNB1. Further studies verify WA as an effective antitumor drug candidate via blocking VCP nuclear localization to impact on the DDR pathway in vivo. Our findings underly the unclear VCP’s role in DDR in a KPNB1-dependent manner and provide an important theoretical basis for developing small-molecule inhibitors targeting this process.

Gasdermin D (GSDMD) serves as a vital mediator of inflammasome-driven pyroptosis. In our study, we have identified NU6300 as a specific GSDMD inhibitor that covalently interacts with cysteine-191 of GSDMD, effectively blocking its cleavage while not affecting earlier steps such as ASC oligomerization and caspase-1 processing in AIM2- and NLRC4-mediated inflammation. On the contrary, NU6300 robustly inhibits these earlier steps in NLRP3 inflammasome, confirming a unique feedback inhibition effect in the NLRP3-GSDMD pathway upon GSDMD targeting. Our study reveals a previously undefined mechanism of GSDMD inhibitors: NU6300 impairs the palmitoylation of both full-length and N-terminal GSDMD, impeding the membrane localization and oligomerization of N-terminal GSDMD. In vivo studies further demonstrate the efficacy of NU6300 in ameliorating dextran sodium sulfate–induced colitis and improving survival in lipopolysaccharide-induced sepsis. Overall, these findings highlight the potential of NU6300 as a promising lead compound for the treatment of inflammatory diseases.

Purpose: Ultrasound (US) risk stratification systems (RSSs) are increasingly being utilized for the optimal management of thyroid nodules, including those with indeterminate cytology. The goal of this study was to evaluate the category-based diagnostic performance of US RSSs in identifying malignancy in indeterminate nodules.Methods: This systematic review and meta-analysis was registered on PROSPERO (CRD42021266195). PubMed, EMBASE, and Web of Science were searched through December 1, 2022. Original articles reporting data on the performance of US RSSs for indeterminate nodules were included. The numbers of nodules classified as true negative, true positive, false negative, and false positive were extracted.Results: Thirty-three studies evaluating 7,225 indeterminate thyroid nodules were included. The diagnostic accuracy was quantitatively synthesized using a Bayesian bivariate model based on the integrated nested Laplace approximation in R. For the intermediate- to high-risk category, the sensitivity levels of the American College of Radiology, the American Thyroid Association, the European Thyroid Association, the Korean Thyroid Association/Korean Society of Thyroid Radiology, and Kwak et al. were found to be 0.80, 0.72, 0.76, 0.96, and 0.97, respectively. The corresponding specificity measurements were 0.36, 0.50, 0.49, 0.28, and 0.17. Furthermore, for the high-risk category, the sensitivity values were 0.40, 0.46, 0.55, 0.47, and 0.10, while the specificity levels were 0.91, 0.90, 0.71, 0.91, and 0.99, respectively.Conclusion: The overall diagnostic performance of the US RSSs was moderate in the differentiation of indeterminate nodules.