Alcohol-associated liver disease (ALD) is a widely prevalent chronic liver disease caused by alcohol overconsumption. However, the pathogenesis of ALD is complex and has not been fully elucidated. Ring finger protein 2 (RNF2) is associated with the occurrence and development of hepatocellular carcinoma (HCC), but its function in ALD has not been explored. In this study, we investigated the role of RNF2 in ALD and its underlying mechanisms. In vivo, an ALD model was established and adeno-associated virus (AAV8-shRNA-RNF2) was used to knock down RNF2. Liver injury, hepatic steatosis, and inflammation were assessed and functional studies were conducted in AML-12 cells and macrophages. The study found that hepatic-specific RNF2 knockdown attenuated EtOH-induced liver steatosis and inflammation. Furthermore, RNF2 knockdown significantly alleviated EtOH-mediated lipid accumulation and inflammation. Additionally, RNF2 interacted with ubiquitin-specific peptidase 7 (USP7) and regulated the phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway. Importantly, inhibition of USP7 or PI3K/AKT signaling pathway suppressed lipid accumulation and inflammation in the ALD model. Our research demonstrated that RNF2 had a novel function of regulating lipid metabolism and inflammation in ALD through its interaction with USP7 and modulation of the PI3K/AKT signaling pathway.

Hepatic ischemia-reperfusion (I/R) injury can cause poor prognosis of liver transplantation and hepatectomy, especially in patients with alcohol-associated liver disease (ALD). Apoptosis is closely related to different stages of liver injury, and the death of hepatocytes caused by endoplasmic reticulum (ER) and mitochondria homeostasis perturbation may be key to liver injury. The receptor tyrosine kinases AXL encoded by the gene axl, is a member of the TAM (TYRO3, AXL, and MERTK) family, which participates in various biological processes by binding to the ligand of growth arrest-specific protein 6 (Gas6). However, whether AXL is involved in apoptosis pathways, and the detailed mechanism in hepatic I/R injury remains unknown. In the present study, we found that total AXL is up-regulated while phosphorylated AXL (p-AXL, the active form of AXL) was down-regulated after I/R in human liver tissues from liver transplantation. Consistently, total AXL was found up-regulated while p-AXL was down-regulated during hepatic I/R injury in mice. Pretreatment with Gas6 increased p-AXL expression, reduced ER stress-associated cell apoptosis, alleviated liver damage, and restored ER and mitochondria ultrastructure during hepatic I/R in mice. Furthermore, the ALD model was established by chronic-plus-binge ethanol feeding to explore the role of AXL in I/R liver injury with ethanol-associated steatosis. We found that ALD mice had a lower p-AXL level and were more susceptible to hepatic I/R injury. Importantly, activated AXL ameliorated liver injury by inhibiting IRE1 and PERK pathway to reduce ER stress-associated apoptosis. In conclusion, activated AXL protects alcohol-associated steatotic liver against I/R injury by inhibiting ER stress and mitochondria-associated apoptosis, suggesting that targeting AXL serves as a potential strategy for liver I/R injury, particularly for marginal liver donors with alcohol-associated steatosis.

Toxoplasma gondii is an opportunistic protozoan parasite that can establish latent infections in humans, causing toxoplasmosis in immunocompromised individuals. Type I interferons (IFN-I), particularly IFN-β, are critical for controlling Toxoplasma gondii infection, but the parasite has evolved various strategies to manipulate the host immune response. Interferon regulatory factor 3 (IRF3) is a key transcription factor that regulates the expression of antiviral genes, including IFN-I and ISGs. Unlike IFN-β, IRF3-activated ISG56 can enhance T. gondii proliferation. Furthermore, STAT6 activation has also been reported to promote the proliferation of Toxoplasma gondii . In this study, we found that GRA3 is highly expressed in the less virulent ME49 strain. Furthermore, we discovered that GRA3 interacted with STING to activate the cGAS/STING pathway. This interaction promotes STING oligomerization and the nuclear translocation of phosphorylated-IRF3, which in turn enhances IFN-β production. GRA3 in ME49 tachyzoites promoted both IRF3-mediated ISG56 expression and STAT6 phosphorylation, thereby enhancing the proliferation of these less virulent parasites. Interestingly, GRA3 enhances parasite proliferation via a mechanism mediated by ISG56 and STAT6, rather than by IFN-β. This study highlights how less virulent strains modulate host immunity to promote T. gondii survival and replication, establish latent infections, and ultimately achieve widespread dissemination in humans.

Encephalitis resulting from acute reactivation of chronic Toxoplasma gondii infection in the central nervous system poses a significant mortality risk in immunodeficient individuals. However, the specific molecular mechanisms underlying this process remain elusive. We constructed the GRA35 gene knockout ME49 strain and compared the differences with wild type ME49 strain. We used the GST-pull down experiment to explore the mechanism of GRA35 promoting neuronal cell apoptosis. We used immunofluorescence, flow cytometry and CCK8 experiments to verify the pathway of GRA35 promoting neuronal cell apoptosis. Our study reveals that wild type ME49 strain promotes neuronal apoptosis in brain following chronic infection activation. Conversely, infection with the ME49^Δgra35 strain leads to a reduced apoptotic response in brain neurons. Furthermore, we demonstrate that GRA35 interacts with RTN1-c, thereby promoting mitochondrial pathway-mediated apoptosis in neurons. Additionally, GRA35 can trigger host cell ER stress-associated apoptosis through the PERK signaling pathway. GRA35 serves as a crucial virulence factor in the pathogenesis of Toxoplasmic encephalitis (TE), which offers potential new therapeutic target and theoretical insights for TE.

Tracheal injury remains a clinically relevant complication during lung isolation for thoracic surgery. Although video double-lumen tubes (VDLTs) improve vi