A preliminary study unveils CISD2 as a ferroptosis-related therapeutic target for recurrent spontaneous abortion through immunological analysis and two-sample mendelian randomization.

Recurrent spontaneous abortion (RSA) affects approximately 1 % of women striving for conception, posing a significant clinical challenge. This study aimed to identify a prognostic signature in RSA and elucidate its molecular mechanisms. Prognostic gene impacts were further assessed in HTR-8/SVneo and human primary extravillous trophoblast (EVT) cells in vitro experiments. A total of 6168 differentially expressed genes (DEGs) were identified, including 3035 upregulated and 3133 downregulated genes. WGCNA pinpointed 8 significant modules and 31 ferroptosis-related DEGs in RSA. Optimal clustering classified RSA patients into three distinct subgroups, showing notable differences in immune cell composition. Six feature genes (AEBP2, CISD2, PML, RGS4, SRSF9, STK11) were identified. The diagnostic model showed high predictive capabilities (AUC: 0.966). Mendelian randomization indicated a significant association between CISD2 levels and RSA (OR: 1.069, P-value: 0.049). Furthermore, the downregulation of CISD2 promotes ferroptosis in HTR-8/SVneo and human primary EVT cells. CISD2 emerged as a pivotal gene in RSA, serving as a ferroptosis-related therapeutic target. The diagnostic model based on gene expression and Mendelian randomization provides novel insights into the pathogenesis of RSA.

Gomisin A enhances the antitumor effect of paclitaxel by suppressing oxidative stress in ovarian cancer.

Gomisin A (GA) is an effective component of Schisandra. The crude extracts of Schisandra chinensis and its active ingredients have been shown to inhibit multidrug resistance in tumour cells. Reactive oxygen species (ROS) have different roles in cancer and may contribute to therapy resistance. The human ovarian cancer (OC) cell lines SKOV3 and A2780, and a mouse model of OC, were used in the present study. MTT assay, colony formation assay, flow cytometry, western blot analysis, and haematoxylin and eosin (H&E) staining were performed to determine the antitumor effect of GA and paclitaxel (PTX) in vitro and in vivo. The ROS inhibitor N­acetyl cysteine (NAC) was used to assess the mechanism underlying the chemosensitizing effects of GA. Notably, the proliferation of OC cells was inhibited by PTX, which could be enhanced by the ROS inhibitor NAC or GA. Treatment with NAC + PTX or GA + PTX enhanced the cell cycle arrest, but not apoptosis, induced by PTX. Moreover, the molecular mechanism underlying this effect may be that GA decreases the levels of ROS in ovarian cancer cells and inhibits cell cycle progression by downregulating the expression of the cell cycle proteins cyclin­dependent kinase 4 and cyclin B1. In conclusion, the combination of PTX and the ROS inhibitor GA may be a novel strategy in OC chemotherapy.

FGFR3 phosphorylates EGFR to promote cisplatin-resistance in ovarian cancer.

Ovarian cancer is a deadly gynecologic cancer, and the majority of patients with ovarian cancer experience relapse after traditional treatment. Cisplatin (DDP) is a common chemotherapeutic drug for ovarian cancer, but many patients acquire DDP-resistance after treatment with long-term chemotherapy. The mechanisms of drug-resistance in ovarian cancer are not clear, and we thus aim to investigate novel targets for DDP-resistant ovarian cancer. Differential analysis, KEGG pathway enrichment and protein interaction networks were employed to identify the key genes related to DDP-resistance in ovarian cancer. Subsequently, cell viability, apoptosis and migration were measured to assess the effect of fibroblast growth factor receptor 3 (FGFR3) on DDP-resistance. Further, Pearson correlation analysis and co-expression analysis were used to explore the downstream pathways of FGFR3, and the function of FGFR3 and its downstream targets were further demonstrated by in vitro and nude mice experiments. FGFR3 were expressed at high levels in DDP-resistant ovarian cancer cells. FGFR3 silencing suppressed the activation of PI3K/AKT pathway and impeded the drug-resistance and development of tumor cells. Afterwards, we found that FGFR3 was co-expressed with epidermal growth factor receptor (EGFR). FGFR3 overexpression elevated EGFR phosphorylation and activated PI3K/AKT signaling. Furthermore, in nude mice, silencing FGFR3 and inhibiting EGFR phosphorylation were observed to promote the therapeutic effect of DDP. In conclusion, FGFR3 overexpression enhances DDP-resistance of ovarian cancer by promoting EGFR phosphorylation and further activating PI3K/AKT pathway. This study may offer promising targets for DDP-resistant ovarian cancer.

Novel role of lncRNA CHRF in cisplatin resistance of ovarian cancer is mediated by miR-10b induced EMT and STAT3 signaling.

Ovarian Cancer (OC) is a highly lethal gynecological cancer which often progresses through acquired resistance against the administered therapy. Cisplatin is a common therapeutic for the treatment of OC patients and therefore it is critical to understand the mechanisms of resistance against this drug. We studied a paired cell line consisting of parental and cisplatin resistant (CR) derivative ES2 OC cells, and found a number of dysregulated lncRNAs, with CHRF being the most significantly upregulated lncRNA in CR ES2 cells. The findings corroborated in human patient samples and CHRF was significantly elevated in OC patients with resistant disease. CHRF was also found to be elevated in patients with liver metastasis. miR-10b was found to be mechanistically involved in CHRF mediated cisplatin resistance. It induced resistance in not only ES2 but also OVCAR and SKOV3 OC cells. Induction of epithelial-to-mesenchymal-transition (EMT) and activation of STAT3 signaling were determined to be the mechanisms underlying the CHRF-miR-10b axis-mediated cisplatin resistance. Down-regulation of CHRF reversed EMT, STAT3 activation and the resulting cisplatin resistance, which could be attenuated by miR-10b. The results were also validated in an in vivo cisplatin resistance model wherein CR cells were associated with increased tumor burden, CHRF downregulation associated with decreased tumor burden and miR-10b again attenuated the CHRF downregulation effects. Our results support a novel role of lncRNA CHRF in cisplatin resistance of OC and establish CHRF-miR-10b signaling as a putative therapeutic target for sensitizing resistant OC cells.