Nuclear factor erythroid 2-related factor 2 promotes radioresistance by regulating glutamate-cysteine ligase modifier subunit and its unique immunoinvasive pattern.

The enzyme glutamate-cysteine ligase modifier subunit (GCLM) serves as the initial rate-limiting factor in glutathione (GSH) synthesis. GSH is the preferred substrate for glutathione peroxidase 4 (GPX4), directly impacting its activity and stability. This study aims to elucidate the expression of GCLM and its correlation with the nuclear factor erythroid 2-related factor 2 (NFE2L2), commonly referred to as NRF2, in esophageal squamous cell carcinoma (ESCC) and further investigate the potential signaling axis of radiotherapy resistance caused by NRF2-mediated regulation of ferroptosis in ESCC. The expression of NRF2, GCLM, and GPX4 in ESCC was analyzed by bioinformatics, and their relationship with ferroptosis was verified through cell function experiments. Their role in radioresistance was then investigated through multiple validation steps. Bioinformatics analysis was employed to determine the immune infiltration pattern of NRF2 in ESCC. Furthermore, the effect of NRF2-mediated massive macrophage M2 infiltration on radiotherapy and ferroptosis was validated through in vivo experiments. In vitro assays demonstrated that overactivated NRF2 promotes radioresistance by directly binding to the promoter region of GCLM. The Tumor Immune Estimation Resource (TIMER) and quanTIseq analyses revealed NRF2 enrichment in M2 macrophages with a positive correlation. Co-culturing KYSE450 cells with M2 macrophages demonstrated that a significant infiltration of macrophages M2 can render ESCC cells resistant to radiotherapy but restore their sensitivity to ferroptosis in the process. Our study elucidates a link between the NRF2-GCLM-GSH-GPX4 signaling axis in ESCC, highlighting its potential as a therapeutic target for antagonistic biomarkers of resistance in the future. Additionally, it provides a novel treatment avenue for ESCC metastasis and radioresistance.

Clinicopathological Features and Survival Prognosis of Patients with Adenocarcinoma of Esophagogastric junction Complicated with Metabol-ic Syndrome / 医学研究杂志

Objective To investigate the clinicopathological features and survival prognosis of adenocarcinoma of esophagogastric junction(AEG)patients with metabolic syndrome(MS).Methods The clinicopathological data of 135 patients who underwent radical gastrectomy for AEG in the First Affiliated Hospital of Xinjiang Medical University from January 2014 to December 2019,40 cases with MS were selected as the case group,and 95 cases without MS as the control group,so as to explore the clinicopathological features and survival prognosis of AEG patients with complicated with MS.Results There were statistically significant differences in the age,body mass index(BMI),fasting blood-glucose,triglyceride and high-density lipoprotein cholesterol between the case group and the control group(P<0.05),while there were no significant differences in the gender,postoperative adjuvant therapy,general type,invasion of nerves,formation of cancer embolus in vessels,degree of differentiation,depth of invasion,lymph node metastasis,expression of human epidermal growth factor receptor 2(HER2)and clinical TNM stage between the two groups(P>0.05).After adjusting for related con-founding factors,multivariate Logistic regression analysis showed that BMI was most closely correlated with AEG patients with MS,and the difference was statistically significant(P<0.001).AEG patients with BMI≥25kg/m2had an increased risk of MS(OR = 1.306,95%CI:1.135-1.501).Survival analysis showed that there was no statistically significant difference in overall survival time between the two groups(χ2 =0.042,P =0.857).Conclusion Advanced age,obesity,hyperglycemia and hyperlipidemia are the typical clinical char-acteristics of AEG patients with MS,among which′BMI is the most closely related,suggesting that the risk of MS is significantly increased in AEG obese patients.