Disulfidptosis, a novel form of regulated cell death, involves cytoskeletal collapse due to excessive disulfide bond formation, linking metabolism and reactive oxygen species to potential cancer therapy targets. Recent multi‐omics studies highlight the prognostic value of disulfidptosis‐related gene (DRG) signatures in pan‐cancers; however, the molecular mechanisms underlying their biological functions and therapeutic relevance remain poorly defined. Herein, a DRG score model is constructed using LASSO Cox regression across 33 cancer types, and a nomogram incorporating the DRG score is developed for prognostic prediction. The tumor microenvironment, mutation profiles, and immunotherapy responses are analyzed. The DRG score serves as an independent prognostic factor across cancers, correlating with poor outcomes and malignant features. Glucose deprivation induces disulfidptosis in SLC7A11 ^high cells (high SLC7A11 expression), especially in cancers with a high DRG score, such as ovarian cancer. Silencing INF2 prevents disulfidptosis and decreases susceptibility to irofulven, which can be reversed by GLUT inhibitors. SLC7A11 knockdown reduces disulfidptosis, restores ATP/NADPH levels, and protects the cytoskeleton under glucose deprivation, whereas INF2 knockdown impairs cell migration. Moreover, the DRG scores predict prognosis and therapeutic responses. The SLC7A11‐INF2 axis regulates disulfidptosis, migration, and drug sensitivity, highlighting its potential as a marker of metabolic vulnerability in ovarian cancer.

MicroRNAs (miRNAs) dysregulation contributes to tumorigenesis, and it is reported that abnormal miR-92a-3p expression participates in multiple cancers’ occurrence and progression. This study focuses on miR-92a-3p’s functions and regulatory mechanism in breast cancer (BC). The current study proved miR-92a-3p expression was enhanced in BC tissues and cells, and its high expression was related to increased TNM stage and larger tumor size of BC patients. Functionally, transfection of miR-92a-3p mimics facilitated BC cell proliferation and metastasis, yet transfection of miR-92a-3p inhibitors functioned oppositely. In addition, BTG2 was verified as a direct miR-92a-3p target in BC cells. This research indicated that miR-92a-3p facilitates BC cell proliferation and metastasis through repressing BTG2 expression. GRAPHICAL ABSTRACT

Brain metastasis (BM) frequently occurs in advanced non-small cell lung cancer (NSCLC) and is associated with poor clinical prognosis. Due to the location of metastatic lesions, the surgical resection is limited and the chemotherapy is ineffective because of the existence of the blood brain barrier (BBB). Therefore, it is essential to enhance our understanding about the underlying mechanisms associated with brain metastasis in NSCLC. In the present study, we explored the RNA-Seq data of brain metastasis cells from the GEO database, and extracted RNA collected from primary NSCLC tumors as well as paired brain metastatic lesions followed by microRNA PCR array. Meanwhile, we improved the in vivo model and constructed a cancer stem cell-derived transplantation model of brain metastasis in mice. Our data indicated that the level of miR-596-3p is high in primary NSCLC tumors, but significantly downregulated in the brain metastatic lesion. The prediction target of microRNA suggested that miR-596-3p was considered to modulate two genes essential in the brain invasion process, YAP1 and IL-8 that restrain the invasion of cancer cells and permeability of BBB, respectively. Moreover, in vivo experiments suggested that our model mimics the clinical aspect of NSCLC and improves the success ratio of brain metastasis model. The results demonstrated that miR-596-3p significantly inhibited the capacity of NSCLC cells to metastasize to the brain. Furthermore, these finding elucidated that miR-596-3p exerts a critical role in brain metastasis of NSCLC by modulating the YAP1-IL8 network, and this miRNA axis may provide a potential therapeutic strategy for brain metastasis.

Pittsburgh modified TNM criteria is one of the prognostic models of orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). In this study, we applied this prognostic system in a series of HCC patients receiving OLT to verify its reliability in the clinical prognostic prediction. The clinical record and follow-up data of 102 patients with HCC underwent OLT was collected. The patients were classified by 3 staging systems: the Pittsburgh Modified TNM Criteria, International Union Against Cancer (UICC) pTNM Staging System, and Milan Criteria. Survival rates of the patients were analyzed using the Kaplan-Meier method and the Log-Rank test, and then the prognostic values of the 3 staging systems were compared. Among the 3 staging systems, the Pittsburgh Modified TNM Criteria showed the best stratification of patients with different prognosis. The overall survival rates of the patients at the Pittsburgh modified TNM stage I, II, III, and IV were 94.4%, 83.3%, 58.2%, and 36.8% at 1 year, and 79.4%, 62.5%, 26.2%, and 10.5% at 3 years, respectively. For those patients exceeding the Milan Criteria, the patients at Pittsburgh stages I and II had a significant higher survival rate than those at Pittsburgh stages III and IV (P<0.001). The Pittsburgh Modified TNM Criteria is a more reliable postoperative staging system than the UICC pTNM staging system for HCC patients receiving OLT. As providing more accurate prognostic classification, it could be reasonable to combine the Milan Criteria for recipient selection.

Background Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and follicular growth arrest. This study investigates the role of a newly identified long non-coding RNA, lncRNA-ZSCAN2-5:15 (HUPCOS), in the dysregulation of androgen metabolism and ovulatory function. Methods Clinical samples from 47 PCOS patients and 68 controls undergoing intracytoplasmic sperm injection were analyzed. Follicular fluid hormone levels and granulosa cell expression of HUPCOS, CYP19 A1, and SMAD4 were measured. A PCOS-like mouse model was established via DHEA injection, and Hupcos overexpression was induced by AAV9, with estrous cycles, hormone levels, and ovarian histology examined. Mechanistic studies in KGN cells included overexpression and knockdown assays, immunoprecipitation, ubiquitination, and dual-luciferase reporter assays. Results PCOS patients showed higher HUPCOS expression (p < 0.01) and testosterone levels (p < 0.0001), and reduced CYP19 A1 in granulosa cells. Hupcos-overexpressing mice showed PCOS-like symptoms, including estrous cycle disturbances and hormonal imbalances. In vitro, HUPCOS overexpression suppressed aromatase expression and estradiol production, while enhancing androstenedione accumulation. Mechanistically, HUPCOS promoted RBPMS ubiquitination, reduced its interaction with SMAD4, and downregulated CYP19 A1 transcription. Co-overexpression of RBPMS and HUPCOS reversed these effects. Conclusions HUPCOS impairs estrogen biosynthesis in PCOS by enhancing RBPMS degradation and disrupting SMAD4-mediated transcription of CYP19 A1. These findings highlight a novel lncRNA-mediated mechanism contributing to hyperandrogenemia and follicular arrest, offering potential targets for PCOS therapy. Graphical Abstract 1. lncRNA HUPCOS is significantly upregulated in granulosa cells of PCOS patients and positively correlates with serum testosterone levels. 2. Overexpression of HUPCOS in mice induces estrous cycle irregularities and PCOS-like ovarian changes. 3. Mechanistically, HUPCOS enhances RBPMS ubiquitination, reducing its interaction with SMAD4 and suppressing CYP19 A1 expression. 4. This HUPCOS-RBPMS-SMAD4 regulatory axis disrupts estrogen biosynthesis and contributes to hyperandrogenism in PCOS.

AC0010 Supplementary methods; Table S1. IC50 values of AC0010 against representative kinases from biochemistry assay and cell-based ELISA assay; Table S2. List of 55 targets tested to assess the off target effect of AC0010 by an in vitro binding assay; Table S3. IC50 values of AC0010 in cell-based assays against targets with inhibition rate larger than 50% in binding assay; Table S4. Inhibitory activities of EGFR TKIs on proliferation of wild-type NCI-H1975, AC0010-resistant NCI-H1975-P1, NCI-H1975-AVR1 and Osimertinib-resistant NCI-H1975-OSR1 cells; Table S5. Inhibitory activities of AC0010 metabolites M7, MII-2 and MII-6 on proliferation of a panel of cell lines; Table S6. Inhibitory activities of AC0010 and its metabolites on IGF-1R in comparison with rociletinib and its metabolites; Table S7. Baseline demographic and clinical characteristics of 25 patients in dose escalation stage up to date