The upregulation of dihydroorotate dehydrogenase (DHODH) redox systems inside tumor cells provides a powerful shelter against lipid peroxidation (LPO), impeding ferroptosis-induced antitumor responses. To solve this issue, we report a strategy to block redox systems and enhance ferroptotic cancer cell death based on a layered double hydroxide (LDH) nanoplatform (siR/IONs@LDH) co-loaded with ferroptosis agent iron oxide nanoparticles (IONs) and the DHODH inhibitor (siR). siR/IONs@LDH is able to simultaneously release IONs and siR in a pH-responsive manner, efficiently generate toxic reactive oxygen species (ROS) via an Fe 2+ -mediated Fenton reaction, and synergistically induce cancer cell death upon the acceleration of LPO accumulation. In vivo therapeutic evaluations demonstrate that this nanomedicine has excellent performance for tumor growth inhibition without any detectable side effects. This work thus provides a new insight into nanomaterial-mediated tumor ferroptosis therapy.

Cancer immunotherapy agents fight cancer via immune system stimulation and have made significant advances in minimizing side effects and prolonging the survival of patients with solid tumors. However, major limitations still exist in cancer immunotherapy, including the inefficiency of immune response stimulation in specific cancer types, therapy resistance caused by the tumor microenvironment (TME), toxicities by the immune imbalance, and short lifetime of stimulator of interferon genes (STING) agonist. Recent advances in nanomedicine have shown significant potential in overcoming the obstacles of cancer immunotherapy. Several nanoscale agents have been reported for cancer immunotherapy, including nanoscale cancer vaccines impacting the STING pathway, nanomaterials reprogramming TME, nano-agents triggering immune response with immune checkpoint inhibitor synergy, ferroptosis-mediated and

Non-neoplastic epithelial disorders of the vulva (NNEDV) are prevalent and refractory gynecological diseases. However, the underlying pathogenesis of these diseases remain unclear. The present study aimed to investigate the expression and significance of cyclin D1, cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase inhibitor P27 (P27) in patients with NNEDV and provide a reference for clinical diagnosis and treatment. Normal vulvar skin samples from patients with perineum repair (control group, n=20) and skin samples from the vulvar lesions of patients with NNEDV (NNEDV group, n=36) were collected. Expression levels of cyclin D1, CDK4 and P27 were assessed in the samples using immunohistochemistry. The expression of each protein was evaluated based on the mean optical density (MOD). The MODs of cyclin D1 and CDK4 were significantly higher in samples of the three pathological types of NNEDV, namely squamous hyperplasia (SH), lichen sclerosus (LS) and mixed SH and LS lesions, compared with those of the control group. The MOD of P27 was lower in samples of the three pathological types of NNEDV than in the control group, although the difference was not statistically significant. No significant differences in the MOD of cyclin D1, CDK4 and P27 were detected among the three pathological types of NNEDV. The ratios of the MOD of cyclin D1 and CDK4 in the prickle cell layer to those in the basal cell layer were significantly higher in the NNEDV group than in the control group. However, the ratio of the MOD of P27 in the prickle cell layer to that in the basal cell layer exhibited no significant difference between the NNEDV and control groups. NNEDV has the potential for malignant transformation. The occurrence and development of NNEDV may be associated with the acceleration of cell proliferation, in which cyclin D1, CDK4 and P27 contribute to regulation of the cell cycle. Therefore, cyclin D1, CDK4 and P27 may be potential targets in the development of new clinical therapeutic drugs for patients with NNEDV.