RESUMO
Ischemic stroke is the primary reason for human disability and death, but the available treatment options are limited. Hence, it is imperative to explore novel and efficient therapies. In recent years, pyroptosis (a pro-inflammatory cell death characterized by inflammation) has emerged as an important pathological mechanism in ischemic stroke that can cause cell death through plasma membrane rupture and release of inflammatory cytokines. Pyroptosis is closely associated with inflammation, which exacerbates the inflammatory response in ischemic stroke. The level of inflammasomes, GSDMD, Caspases, and inflammatory factors is increased after ischemic stroke, exacerbating brain injury by mediating pyroptosis. Hence, inhibition of pyroptosis can be a therapeutic strategy for ischemic stroke. In this review, we have summarized the relationship between pyroptosis and ischemic stroke, as well as a series of treatments to attenuate pyroptosis, intending to provide insights for new therapeutic targets on ischemic stroke.
Assuntos
Inflamassomos , AVC Isquêmico , Piroptose , Piroptose/efeitos dos fármacos , Humanos , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/imunologia , AVC Isquêmico/metabolismo , Animais , Inflamassomos/metabolismo , Transdução de Sinais , Terapia de Alvo MolecularRESUMO
Ferroptosis, an iron-dependent form of programmed cell death, is a promising strategy for cancer treatment. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader and a promising target for cancer therapeutics. However, the role of BRD4 in ferroptosis is controversial and the value of the interaction between BRD4 inhibitors and ferroptosis inducers remains to be explored. Here, we found that BRD4 inhibition greatly enhanced erastin-induced ferroptosis in different types of cells, including HEK293T, HeLa, HepG2, RKO, and PC3 cell lines. Knocking down BRD4 in HEK293T and HeLa cells also promoted erastin-induced cell death. BRD4 inhibition by JQ-1 and I-BET-762 or BRD4 knockdown resulted in substantial accumulation of reactive oxygen species (ROS) in both HEK293T and HeLa cells. The effect of BRD4 inhibition on ferroptosis-associated genes varied in different cells. After using BRD4 inhibitors, the expression of FTH1, Nrf2, and GPX4 increased in HEK293T cells, while the levels of VDAC2, VDAC3, and FSP1 decreased. In HeLa cells, the expression of FTH1, VDAC2, VDAC3, Nrf2, GPX4, and FSP1 was reduced upon treatment with JQ-1 and I-BET-762. Consistently, the level of FSP1 was greatly reduced in HEK293T and HeLa cells with stable BRD4 knockdown compared to control cells. Furthermore, ChIP-sequencing data showed that BRD4 bound to the promoter of FSP1, but the BRD4 binding was greatly reduced upon JQ-1 treatment. Our results suggest that ROS accumulation and FSP1 downregulation are common mechanisms underlying increased ferroptosis with BRD4 inhibitors. Thus, BRD4 inhibitors might be more effective in combination with ferroptosis inducers, especially in FSP1-dependent cancer cells.