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A novel non-nad-based PARP1 inhibitor, Japoflavone B, triggered Caspase-3/GSDME-mediated pyroptosis through ROS/p38/p53 pathway in NSCLC

ABSTRACT: It’s an effective anti-cancer strategy to study natual products for activating GSDME-mediated pyroptosis through targeting PARP-1 in NSCLC. Previously, we found that a novel flavonoid Japoflavone B (JFB) has exhibited an excellent inhibitory activity against cancer cell proliferation in vitro study, but its in vivo and mechanism study are still unknown. Herein, JFB could specifically inhibit the proliferation of NSCLC cells, but not normal lung epithelial cells. JFB induced inflammatory pyroptosis through the activation of caspase-3 and GSDME cleavage. JFB also activated caspase-3/7/9 activities and triggered mitochondria-mediated apoptosis. Its inhibitory activity would be significantly reversed with the caspase-3 or GSDME deficiencies and their specific inhibitors. JFB could targetedly inhibit PARP-1 activity, and promote DNA damage and ROS accumulation. Meanwhile, JFB could significantly promote p-p38 and p53 expression. Then, JFB induced cell cycle G2/M arrest by reprogramming the expression of cyclins, CDKs and CKIs. Moreover, its cytotoxicity could be dramatically reversed with the ROS scavenger and p38 inhibitor. In vivo, JFB exhibited a comparable anti-tumor activity to that of Dox with no significant tissue toxicity. Our data firstly revealed that JFB functions as a selective and non-NAD-based PARP inhibitor with high affinity and low toxicology, which makes it potential to develop as a lead anti-cancer compound. As well, JFB promoted caspase-3/GSDME-mediated pyroptosis through ROS/p38/p53 pathway in NSCLC cells. Our study was further enriched the specific mechanism that PARP inhibitor could trigger caspase-3/GSDME-mediated pyroptosis through ROS/p38/p53 pathway in NSCLC cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281636 | GEO | 2025/11/09

REPOSITORIES: GEO

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Project description:BACKGROUND: Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disease with a poor prognosis. Accumulating studies have reported that gut microbiota contributes to the pathophysiology of several central nervous system diseases. However, whether SAH can change gut microbiota composition and affected gut microbiota is involved in the development of secondary brain injury following SAH remains unclear.METHODS: A retrospective case-control study was performed in unruptured intracranial aneurysm (UIA, CTL) and ruptured intracranial aneurysm (SAH) patients. Patients' fecal and serum samples were collected and sequenced by metagenome and metabolome. The experimental SAH mice models were established, and their feces and serum were also analyzed by 16S rRNA and metabolic sequencing. Fecal microbiota from SAH patients and mice was transplanted to ABX mice to investigate the relationship between the gut microbiota and secondary brain injury following SAH.RESULTS: SAH seriously influenced gut microbiota composition and significantly increased the relative abundance of the genus Escherichia. SAH also considerably reduced the production of gut microbiota-derived butyric acid. Furthermore, SAH-induced gut microbiota dysbiosis aggravated brain injury and cognitive deficits in ABX mice by promoting inflammatory response. Sodium butyrate (NaB) administration protected against secondary brain injury following SAH by inhibiting pyroptosis-related neuroinflammation, which is mediated by NLRP1/Caspase-1/GSDMD and Caspase-3/GSDME signaling pathways. NaB drinking pretreatment also alleviated secondary brain injury following SAH by increasing the relative abundance of butyric acid-producing bacteria, such as Dubosiella and Faecalibaculum, and decreasing the Escherichia abundance.CONCLUSION: SAH contributed to gut microbiota dysbiosis and changed gut microbiota exacerbated secondary brain injury after SAH. Supplement with gut microbiota-derived butyric acid protected against brain injury following SAH by inhibiting NLRP1/Caspase-1/GSDMD and Caspase-3/GSDME-mediated neuronal pyroptosis. Linked studies:UPLC-MS/MS assays of human samples are reported in this study.UPLC-MS/MS assays of  murine samples are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS9100' rel='noopener noreferrer' target='_blank'>MTBLS9100</a>.

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A novel non-nad-based PARP1 inhibitor, Japoflavone B, triggered Caspase-3/GSDME-mediated pyroptosis through ROS/p38/p53 pathway in NSCLC

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