Agathic acid derivatives including a novel ferroptosis inhibitor from the fungus Penicillium thomii.

Ferroptosis contributes to neurodegenerative disorders, ischemic injuries, tumor progression, and acute organ dysfunction. Targeting its core mechanisms, lipid peroxidation and iron overload, ferroptosis inhibitors may offer innovative therapeutic strategies. In our study, chemical investigation of the fungus Penicillium thomii led to 14 agathic acid derivatives, including a new 2,3-seco-labdane (1), two new 19-nor-2,3-seco-labdanes (2 and 3), a new 3,19-dinor-2,3-seco-labdane (4), a new 19-nor labdane (5), and a new agathic acid analogue (6). The structures were determined by comprehensive spectroscopic analysis combined with ECD calculations. Compounds 2-4 are rare nor-2,3-seco-labdanes, with 4 being the first 3,19-dinor-2,3-seco-labdane found in nature. Compounds 1-3, 8, and 9, featuring a 2,3-seco-labdane skeleton with a 3-methyl-hydrofuran unit, represent five of the six members of these analogues. Inspired by reported anti-ferroptotic activity of the structurally related labdane andrographolide, these compounds were evaluated for ferroptosis inhibitions. Compound 3 exhibited potent suppression of RSL3-induced ferroptosis with an EC50 of 2.1 ± 0.6 μM. Mechanistic studies revealed that compound 3 effectively suppressed lipid peroxidation, as evidenced by normalized MDA levels and attenuated lipid radical generation. Concurrently, it restored cellular antioxidant defenses through upregulation of GPX4/SLC7A11 axis and enhancement of Nrf2 signaling. Specifically, compound 3 promoted Nrf2 nuclear translocation, inducing transcriptional upregulation of the cytoprotective effectors HO-1 and NQO1. This study established 3 as a potent ferroptosis inhibitor, with unique structural features positioning it as a promising lead candidate for ferroptosis-associated pathologies.