Background and Purpose: Neuroprotective strategy targeting ferroptosis is currently considered a promising therapeutic approach for neurodegenerative diseases (NDDs). Herpotrichones showed potential the neuroprotective activity with low toxicity. The current study aimed to find new herpotrichone neuroprotectants and investigate their neuroprotective mechanism in vitro and in vivo. Experimental Approach: Comprehensive separation methods were used to isolate new herpotrichone analogues. The H2O2, RSL3, 6-OHDA-induced PC12 cells and LPS-induced BV-2 cells were used to assess the potential neuroprotective effect of compounds. UV-vis spectroscopy was used to determine the cell-free antioxidant and iron-chelating capacity. Western blotting, immunofluorescence, quantitative PCR, flow cytometry and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the activation of the antioxidative elements and the regulation of the ferroptosis factors in cell cultures and in zebrafish larvae. Key Results: Herpotrichone A (He-A) and a new herpotrichone analogue with a new pentacyclic 6/6/6/6/3 skeleton exhibited significantly the neuroprotective effect in cell cultures. He-A activated antioxidative elements and modulated SLC7A11 pathways. The decreased lipid ROS levels but increased GSH level showed the anti-ferroptosis effect of He-A. The increased cell viability in RSL3-induced PC12 cells and the improvement of locomotor in 6-OHDA-induced zebrafish larvae indicated that He-A possessed protective ability against neuronal damage. Conclusion and Implications: This study identifies a novel compound He-A that protects against neuronal damage through activating Nrf2 pathway to upregulate antioxidative elements and increasing the expressions of SLC7A11, FTL and FTH1 in vitro and in vivo, which supports the development of He-A as a new neuroprotective agent targeting ferroptosis.

Background and Purpose: Pancreatic cancer is an exceptionally fatal disease. However, therapeutic drugs for pancreatic cancer have presented a serious shortage over the past few decades. Signal Transducer and Activator of Transcription-3 (STAT3) is persistently activated in many human cancers where it promotes tumor development and progression. Natural products serve as an inexhaustible source of anticancer drugs. Here, we identified the natural product Trienomycin A (TA), an ansamycin antibiotic, as a potential inhibitor of the STAT3 pathway with potent activity against pancreatic cancer. Experimental Approach: Utilizing the STAT3-luciferase (STAT3-luc) reporter system, we found that TA potently inhibits the transcriptional activity of STAT3. We subsequently investigated in vitro and in vivo inhibitory activity of TA against pancreatic cancer and its potential mechanism by using the molecular docking, SPR assay, MTS assay, colony formation assay, transwell migration/invasion assay, flow cytometric analysis, immunofluorescence staining, quantitative real-time PCR, western blotting, tumor xenograft model, H&E staining and immunohistochemistry. Key Results: TA directly bound to STAT3 and inhibited STAT3 (Tyr705) phosphorylation, leading to the inhibition of the STAT3 pathway. TA significantly inhibited the colony formation, proliferation, migration and invasion of pancreatic cancer cell lines. TA dramatically blocked pancreatic tumor growth. More importantly, TA did not show obvious toxicity at the effective dose in mice. Conclusions and Implications: TA exhibits antineoplastic activity by suppressing the STAT3 activation in pancreatic cancer. TA could be a novel therapeutic candidate for pancreatic cancer by blocking the STAT3 pathway.