Background: Nod-like receptor protein 3 (NLRP3) inflammasome is a crucial contributor in the inflammatory process during cerebral ischemia/reperfusion (I/R) injury. ATF4 plays a pivotal role in the pathogenesis of cerebral I/R injury, however, its function and underlying mechanism are not fully characterized yet. In the current study, we examined whether ATF4 ameliorates cerebral I/R injury by inhibiting NLRP3 inflammasome activation and whether mitophagy is involved in this process. In addition, we explored the role of parkin in ATF4-mediated protective effects. Method: To address these issues, healthy male adult Sprague-Dawley rats were exposed to middle cerebral artery occlusion for 1 h followed by 24 h reperfusion. Adeno-associated virus (AAV) and siRNA were injected into rats to overexpress and knockdown ATF4 expression, respectively. After pretreatment with AAV, mdivi-1(mitochondrial division inhibitor-1) was injected into rats to block mitophagy activity. Parkin expression was knockdown using specific siRNA after AAV pretreatment. Result: Data showed that ATF4 overexpression induced by AAV was protective against cerebral I/R injury, as evidenced by reduced cerebral infraction volume, decreased neurological scores and improved outcomes of HE and Nissl staining. In addition, overexpression of ATF4 gene was able to up-regulate Parkin expression, enhance mitophagy activity and inhibit NLRP3 inflammasome-mediated inflammatory response. ATF4 knockdown induced by siRNA resulted in the opposite effects. Furthermore, ATF4-mediated inhibition of NLRP3 inflammasome activation was strongly affected by mitophagy blockage upon mdivi-1 injection. Besides, ATF4-mediated increase of mitophagy activity and inhibition of NLRP3 inflammasome activation were effectively reversed by Parkin knockdown using siRNA. Conclusion: Our study demonstrated that ATF4 is able to alleviate cerebral I/R injury by suppressing NLRP3 inflammasome activation through parkin-dependent mitophagy activity. These results may provide a new strategy to relieve cerebral I/R injury by modulating mitophagy-NLRP3 inflammasome axis.

The metastasis of lung cancer represents a significant factor contributing to the failure of clinical treatment, and the mechanisms involved are intricate and not yet completely elucidated. Intermediate filaments, which constitute a key element of the cytoskeleton, function not only as diagnostic markers but also play a role in malignant processes, including tumor proliferation, apoptosis, and migration. The intermediate filament IFFO1 is essential for genomic stability, and its expression level serves as a prognostic indicator in various tumors. However, the functional contributions of IFFO1 in tumor progression remain inadequately understood. Our study revealed that IFFO1 is downregulated in lung cancer patients and is correlated with a poorer prognosis. The depletion of IFFO1 led to enhanced tumor proliferation both in vitro and in vivo, as well as increased cellular migration, alterations in the cytoskeleton and modifications in GTPase-mediated signal transduction. Mechanically, IFFO1 was found to interact directly with the GTPase-related scaffold IQGAP3 through the 2 A coiled-coil domain, which was critical for the inhibition of cellular mobility. Moreover, the increased cell migration observed in IFFO1-deficient cells was substantiated as being facilitated by IQGAP3. Finally, IFFO1 was shown to inhibit the association of IQGAP3 with its effector Cdc42 in a dose-dependent manner. Our study demonstrates the multifaceted roles of IFFO1 in lung cancer by modulating the IQGAP3-Cdc42 axis and suggests the potential for identifying tumor targets through the examination of intermediate filament networks and their associated co-factors.

Uterine corpus endometrial carcinoma (UCEC) is a significant cause of cancer-related mortality among women worldwide. Prior research has demonstrated an association between cyclin-dependent kinase inhibitor 2 A (CDKN2A) and various tumors. As a member of the INK4 family, CDKN2A is involved in cell cycle regulation by controlling CDKs. In the present study, bioinformatics was used to analyze public datasets. The expression levels, signaling pathways, and copy number variations of CDKN2A in UCEC were explored, along with its immune cell subset associations. CDKN2A expression was found to be elevated in UCEC, particularly in the signaling pathways involved in cell proliferation and inflammation. Analysis of somatic copy number alterations in the TCGA (The Cancer Genome Atlas)-UCEC dataset revealed a connection between CDKN2A and drug metabolism in UCEC. Assessment of the relationship between CDKN2A and genes involved in immunotherapy for UCEC patients showed a negative correlation between CDKN2A and CD8⁺ T cell activity, as well as IL-2 and TP53. Collectively, these insights suggest that CDKN2A may be a potential biomarker for prognosis and treatment strategies in UCEC.