Discovery of a novel anti-ischemic acute kidney injury candidate from pestaphilones, a new subtype of azaphilones derived from marine fungus.

Acute kidney injury (AKI), especially ischemic AKI, remains an urgent unmet clinical need, and the discovery of novel drug leads from marine natural products is a crucial strategy for developing innovative AKI therapeutics. From the marine fungus Neopestalotiopsis sp. SCSIO-NS422, 37 pestaphilones were isolated and structurally elucidated as a new subtype of azaphilones characterized by C-9 methylation, with 27 of them being new compounds. Through high-content screening in the library containing 62 azaphilones, new pestaphilone U (PPU) was identified as the most potent anti-ischemic AKI agent, with quantitative structure-activity relationship analysis revealing C-9 methylation as the critical pharmacophore. Furthermore, integrated in vivo and in vitro validation, along with transcriptomic analysis, demonstrated that PPU functioned as a PPARδ (peroxisome proliferator-activated receptor δ) agonist and exerted therapeutic effects against ischemic AKI by modulating reactive oxygen species (ROS). In addition, PPU demonstrated desirable pharmacokinetic characteristics and excellent druggable potential (47.6% oral bioavailability). Collectively, our findings revealed that pestaphilones presented a novel privileged scaffold with anti-ischemic AKI properties, also highlighting PPU as a promising candidate for the treatment of ischemic AKI.