Alzheimer’s disease (AD) is the most common dementia. It is known that women with one ApoE4 allele display greater risk and earlier onset of AD compared with men. In mice, we previously showed that follicle–stimulating hormone (FSH), a gonadotropin that rises in post–menopausal females, activates its receptor FSHR in the hippocampus, to drive AD–like pathology and cognitive impairment. Here we show in mice that ApoE4 and FSH jointly trigger AD-like pathogenesis by activating C/EBPβ/δ-secretase signaling. ApoE4 and FSH additively activate C/EBPβ/δ-secretase pathway that mediates APP and Tau proteolytic fragmentation, stimulating Aβ and neurofibrillary tangles. Ovariectomy-provoked AD-like pathologies and cognitive defects in female ApoE4-TR mice are ameliorated by anti-FSH antibody treatment. FSH administration facilitates AD-like pathologies in both young male and female ApoE4-TR mice. Furthermore, FSH stimulates AD-like pathologies and cognitive defects in ApoE4-TR mice, but not ApoE3-TR mice. Our findings suggest that in mice, augmented FSH in females with ApoE4 but not ApoE3 genotype increases vulnerability to AD-like process by activating C/EBPβ/δ-secretase signalling.

Glioblastoma multiforme, the most prevalent and aggressive brain tumour, has a poor prognosis. The molecular mechanisms underlying gliomagenesis remain poorly understood. Therefore, molecular research, including various markers, is necessary to understand the occurrence and development of glioma. Weighted gene co-expression network analysis (WGCNA) was performed to construct a gene co-expression network in TCGA glioblastoma samples. Gene ontology (GO) and pathway-enrichment analysis were used to identify significance of gene modules. Cox proportional hazards regression model was used to predict outcome of glioblastoma patients. We performed weighted gene co-expression network analysis (WGCNA) and identified a gene module (yellow module) related to the survival time of TCGA glioblastoma samples. Then, 228 hub genes were calculated based on gene significance (GS) and module significance (MS). Four genes (OSMR + SOX21 + MED10 + PTPRN) were selected to construct a Cox proportional hazards regression model with high accuracy (AUC = 0.905). The prognostic value of the Cox proportional hazards regression model was also confirmed in GSE16011 dataset (GBM: n = 156). We developed a promising mRNA signature for estimating overall survival in glioblastoma patients.

Brain-derived neurotrophic factor (BDNF) and its tropomyosin-related kinase B receptor (TrkB) are expressed in human osteoblasts and mediate fracture healing. BDNF/TrkB signaling activates Akt that phosphorylates and inhibits asparagine endopeptidase (AEP), which regulates the differentiation fate of human bone marrow stromal cells (hBMSC) and is altered in postmenopausal osteoporosis. Here we show that R13, a small molecular TrkB receptor agonist prodrug, inhibits AEP and promotes bone formation. Though both receptor activator of nuclear factor kappa-Β ligand (RANK-L) and osteoprotegerin (OPG) induced by ovariectomy (OVX) remain comparable between WT and BDNF+/− mice, R13 treatment significantly elevates OPG in both mice without altering RANKL, blocking trabecular bone loss. Strikingly, both R13 and anti-RANK-L exhibit equivalent therapeutic efficacy. Moreover, OVX increases RANK-L and OPG in WT and AEP KO mice with RANK-L/OPG ratio lower in the latter than the former, attenuating bone turnover. 7,8-DHF, released from R13, activates TrkB and its downstream effector CREB, which is critical for OPG augmentation. Consequently, 7,8-DHF represses C/EBPβ/AEP pathway, inhibiting RANK-L-induced RAW264.7 osteoclastogenesis. Therefore, our findings support that R13 exerts its therapeutic efficacy toward osteoporosis via inhibiting AEP and escalating OPG.

BDNF/TrkB neurotropic pathway, essential for neural synaptic plasticity and survival, is deficient in neurodegenerative diseases including Alzheimer’s disease (AD). Our previous works support that BDNF diminishes AD pathologies by inhibiting delta-secretase, a crucial age-dependent protease that simultaneously cleaves both APP and Tau and promotes AD pathologies, via Akt phosphorylation. Small molecular TrkB receptor agonist 7,8-dihydroxyflavone (7,8-DHF) binds and activates the receptor and its downstream signaling, exerting therapeutic efficacy toward AD. In the current study, we optimize 7,8-DHF pharmacokinetic characteristics via medicinal chemistry to obtain a synthetic derivative CF₃CN that interacts with the TrkB LRM/CC2 domain. CF₃CN possesses improved druglike features, including oral bioavailability and half-life, compared to those of the lead compound. CF₃CN activates TrkB neurotrophic signaling in primary neurons and mouse brains. Oral administration of CF₃CN blocks delta-secretase activation, attenuates AD pathologies, and alleviates cognitive dysfunctions in 5xFAD. Notably, chronic treatment of CF₃CN reveals no demonstrable toxicity. Hence, CF₃CN represents a promising preclinical candidate for treating the devastating neurodegenerative disease.

Solid tumors start as a local disease, but some are capable of metastasizing to the lymph nodes and distant organs. The hypoxic microenvironment, which is critical during cancer development, plays a key role in regulating cancer progression and metastasis. However, the molecular mechanisms mediating the disseminated cancer cell metastasis remain incompletely understood. Here, we show that C/EBPβ/AEP signaling that is upregulated in breast cancers mediates oxidative stress and lung metastasis, and inactivation of asparagine endopeptidase (AEP, also known as legumain) robustly regulates breast cancer reactive oxygen species (ROS) and metastasis. AEP, a protease activated in acidic conditions, is overexpressed in numerous types of cancer and promotes metastasis. Employing a breast cancer cell line MDA-MD-231, we show that C/EBPβ, an oxidative stress or inflammation-activated transcription factor, and its downstream target AEP mediate ROS production as well as migration and invasion in cancer cells. Deficiency of AEP in the MMTV-PyMT transgenic breast cancer mouse model significantly regulates oxidative stress and suppresses lung metastasis. Administration of an innovative AEP inhibitor substantially mitigates ROS production and cancer metastasis. Hence, our study demonstrates that pharmacologic inhibition of AEP activity might provide a disease-modifying strategy to suppress cancer metastasis.

Subarachnoid hemorrhage (SAH) is a serious and common disease and accounts for about 10 % of acute stroke cases. BRCA-associated protein 1 (BAP1) belongs to the ubiquitin C-terminal hydrolases (UCHs) family, which plays an important role in cell metabolism and cell death, but its role in early brain injury (EBI) after SAH requires further study. Forkhead box protein O3a (FOXO3a) is a transcription factor involved in the regulation of cellular function and survival in the nervous system, including the oxidative stress response and neuronal death. This study aimed to explore the effect of FOXO3a and BAP1 on neuronal ferroptosis in the pathogenesis of EBI after SAH. In this study, the overexpression of BAP1 significantly inhibited GPX4 expression and exacerbated the degree of lipid peroxidation and ferroptosis in neurons after SAH. BAP1 regulated the transcription level of the SLC7A11 promoter by H2Aub. FOXO3a could transcriptionally regulate BAP1 to influence the levels of SLC7A11 and GPX4, and mediate lipid peroxidation and neuronal ferroptosis after SAH. Silencing FOXO3 and BAP1 significantly improved neurological deficit and cerebral edema, and reduced oxidative stress damage in SAH mice. After SAH, BAP1 could directly bind to the FKH-DBD + NLS domain located in FOXO3a protein through the UCH domain, and mediates deubiquitination of FOXO3a protein by the K48 site to maintain the stability of FOXO3a. Our findings elucidate the impact of FOXO3a and BAP1 on SLC7A11-related ferroptosis following SAH both in vivo and in vitro, and the inhibition of the FOXO3a-BAP1 axis can significantly attenuate neuronal damage and ferroptosis in EBI after SAH.