Cynarin alleviates acetaminophen-induced acute liver injury through the activation of Keap1/Nrf2-mediated lipid peroxidation defense via the AMPK/SIRT3 signaling pathway.

Overdose of Acetaminophen (APAP) is a major contributor to acute liver injury (ALI), a complex pathological process with limited effective treatments. Emerging evidence links lipid peroxidation to APAP-induced ALI. Cynarin (Cyn), a hydroxycinnamic acid derivative, exhibits liver protective effects, but whether it mitigates APAP-induced ALI is unclear. Our aim was to verify the protective impact of Cyn on APAP-induced ALI and elucidate the molecular mechanisms governing this process. Herein, the regulation of the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) interaction was determined to be a novel mechanism underlying this protective impact of Cyn against APAP-induced ALI. Nrf2 deficiency increased the severity of APAP-induced ALI and lipid peroxidation and counteracted the protective effect of Cyn against this pathology. Additionally, Cyn promoted the dissociation of Nrf2 from Keap1, enhancing the nuclear translocation of Nrf2 and the transcription of downstream antioxidant proteins, thereby inhibiting lipid peroxidation. Molecular docking demonstrated that Cyn bound competitively to Keap1, and overexpression of Keap1 reversed Nrf2-activated anti-lipid peroxidation. Additionally, Cyn activated the adenosine monophosphate-activated protein kinase (AMPK)/sirtuin (SIRT)3 signaling pathway, which exhibits a protective effect on APAP-induced ALI. These findings propose that Cyn alleviates APAP-induced ALI by enhancing the Keap1/Nrf2-mediated lipid peroxidation defense via activation of the AMPK/SIRT3 signaling pathway.

Unravelling diagnostic clusters and immune landscapes of disulfidptosis patterns in gastric cancer through bioinformatic assay.

Disulfidptosis is a novel type of cell death mediated by SLC7A11-induced disulfide stress. Gastric cancer (GC) is a common malignant gastrointestinal tumor. Existing evidence shows that SLC7A11 can regulate cell death and improve the progression of GC, suggesting disulfidptosis may exist in the pathological process of GC. However, the underlying functions of disulfidptosis regulators in GC remain unknown. The dataset of GSE54129 was screened to comprehensively investigate the disulfidptosis-related diagnostic clusters and immune landscapes in GC. Totally 15 significant disulfidptosis regulators were identified via difference analysis between GC samples and controls. Then random forest model was utilized to assess their importance score (mean decrease Gini). Then a nomogram model was constructed, which could offer benefit to patients based on our subsequent decision curve analysis. All the included GC patients were divided into 2 disulfidptosis subgroups (clusterA and clusterB) according to the significant disulfidptosis regulators in virtue of consensus clustering analysis. The disulfidptosis score of each sample was calculated through PCA algorithms to quantify the disulfidptosis subtypes. Patients from clusterB exhibited lower disulfidptosis scores than those of patients in clusterA. In addition, we found that the cases in clusterB were closely associated with the immunity of activated CD4 T cell, etc., while clusterA was linked to immature dendritic cell, mast cell, natural killer T cell, natural killer cell, etc., which has a higher disulfidptosis score. Therefore, disulfidptosis regulators play an important role in the pathological process of GC, providing a promising marker and an immunotherapeutic strategy for future GC therapy.