Background: Glutathione peroxidase 4 (GPX4), an important factor regulating redox homeostasis, plays an important role in tumor microenvironment and progression. However, the role of GPX4 in gastric cancer (GC) is unclear.

Tamoxifen resistance is a common and difficult problem in the clinical treatment of breast cancer (BC). As a novel antitumor agent, Micheliolide (MCL) has shown a better therapeutic effect on tumours; however, little is known about MCL and its role in BC therapy. With tamoxifen stimulation, drug‐resistant BC cells MCF7TAMR and T47DTAMR obtained a high oxidative status and Amidohydrolase 1 (ASAH1) was abnormally activated. The inhibition of ASAH1 rescued the sensitivity of resistant cells to tamoxifen. We found that MCL inhibited the expression of ASAH1 and cell proliferation, especially in MCF7TAMR and T47DTAMR cells. The high oxidative stress status of resistant cells stimulated the expression of ASAH1 by positively regulating AKT, which was restrained by MCL. MCL activated NRF2 by directly binding to KEAP1 and promoting the antioxidant level of tamoxifen‐resistant (TAMR) cells. In addition, ACT001, the prodrug of MCL, significantly inhibited the tumour growth of TAMR cells in preclinical xenograft tumour models. In conclusion, ASAH1 mediates tamoxifen resistance in ER‐positive BC cells. MCL could activate the cellular antioxidant system via NRF2/KEAP1 and inhibit ASAH1 expression through the ROS/AKT signalling pathway, thus suppressing cell proliferation. MCL could be used as a potential treatment for TAMR‐BC.

Background: Gastric cancer (GC) is one of the most common malignancies worldwide. Transmembrane protein 119 (TMEM119), a member of the transmembrane protein family, has been increasingly linked to cancer progression, with accumulating evidence indicating that its overexpression correlates with poor prognosis in several kinds of human cancers. Nevertheless, the relationship between TMEM119 expression and prognosis in GC patients remains unclear. This study aims to evaluate the association of TMEM119 expression levels and clinical outcomes in GC. Methods: Immunofluorescence was performed to assess TMEM119 expression in GC tissues and matched adjacent non-tumorous tissues. Patients’ survival data were collected via scheduled follow-up. Gene expression profiles of TMEM119 and corresponding clinical characteristics of GC patients were obtained from the GSE84437 dataset and the Asian Cancer Research Group (ACRG) database. The Chi-squared test and Fisher’s exact test were used to analyze the correlations between TMEM119 expression and clinicopathological characteristics. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors affecting survival in GC patients. Results: Immunofluorescence staining revealed high expression of TMEM119 in GC tissues. Elevated TMEM119 levels were significantly correlated with poorer prognosis in our institutional cohort of GC patients. This finding was consistently validated in both European and Asian populations, supporting the independence of TMEM119 prognostic value from ethnic variations and underscoring its potential as a cross-population validated prognostic biomarker for GC prognosis. Univariate and multivariate analyses further confirmed that high TMEM119 expression is an independent risk factor for adverse outcomes in GC patients. Conclusions: TMEM119 expression is consistently elevated in GC tissues and is inversely associated with patient prognosis, suggesting its potential value as a prognostic biomarker.

Background: Gastric signet-ring cell carcinoma (GSRCC) is a distinct subtype of gastric cancer characterized by unique biological features, leading to low rates of early diagnosis, poor prognosis, and limited response to chemotherapy and immunotherapy. Effective targeted therapies for GSRCC remain scarce. Given these treatment challenges and the potential efficacy of antibody-drug conjugates (ADCs) in clinical settings, this study focuses on identifying novel ADCs with significant potential to improve the treatment outcomes of GSRCC. Methods: We conducted a comprehensive bioinformatics analysis of GSRCC using multi-omics data (including transcriptomics and proteomics) and identified the poliovirus receptor (PVR) as a potential therapeutic target for GSRCC. We selected deruxtecan (DXd) as an effective carrier for developing an ADC targeting GSRCC. The synthesized PVR monoclonal antibody-DXd complex (PVR-DXd) has a drug-to-antibody ratio (DAR) of 4. Results: PVR-DXd demonstrated potent antitumor activity in a human GSRCC xenograft model, effectively eliminating tumors while sparing normal tissue, highlighting its potential as a novel and impactful targeted therapy for this aggressive subtype of gastric signet ring cell carcinoma. Conclusions: This preliminary study supports the further development of PVR-DXd as a candidate therapy for advanced GSRCC.