Discovery of a Hepatoprotective Trinor-Sesterterpenoid from the Marine Fungus Talaromyces sp. Against Hepatic Ischemia-Reperfusion Injury

A new trinor-sesterterpenoid penitalarin D (<b>1</b>), with a 3,6-dioxabicyclo[3.1.0]hexane moiety, as well as two known compounds, penitalarin C (<b>2</b>) and nafuredin A (<b>3</b>), were obtained from the mangrove sediment-derived <i>Talaromyces</i> sp. SCSIO 41412. Their structures were determined by detailed NMR, MS spectroscopic analyses, and ECD calculations. Penitalarin D (<b>1</b>) and nafuredin A (<b>3</b>) showed toxicity or no toxicity against HepG2 cells at a concentration of 200 μM. The transcriptome sequencing and bioinformatics analysis revealed that <b>3</b> could be effective by regulating ferroptosis pathways in HepG2 cells, which was subsequently validated by RT-qPCR, demonstrating significant upregulation of ferroptosis-related genes. Pre-treatment with <b>3</b> could mitigate hypoxia-reoxygenation-induced damage in the oxygen glucose deprivation/reperfusion (OGD/R) cell model. Given the structural similarity of compounds <b>1</b>, <b>2</b>, and <b>3</b>, we also screened compounds <b>1</b> and <b>2</b> in an AML12 OGD/R model. As no significant activity was observed, compound <b>3</b> was selected for subsequent in vivo studies. Subsequently, in vivo experiments demonstrated that <b>3</b> could significantly decrease pro-inflammatory cytokines and display the hepatoprotective effects against hepatic ischemia-reperfusion injury (HIRI). These findings identified nafuredin A (<b>3</b>) as a promising hepatoprotective agent for new drug development.