Talarotetramates A–F, Decalin-Containing Tetramic Acids as Ferroptosis Inhibitors from the Deep-Sea-Derived Fungus <i>Talaromyces</i> sp. gb505

Talarotetramates A-F (<b>1</b>-<b>6</b>), six novel 3-decalinoyltetramic acids (3-DTAs), were discovered from the deep-sea-derived fungus <i>Talaromyces</i> sp. gb505, along with a structurally related analogue, talaroconvolutin A (<b>7</b>). Their structures were elucidated by comprehensive analysis of NMR spectra, HRESIMS, and quantum chemical calculations of ECD and NMR data. Compounds <b>1</b>-<b>4</b> represent the first examples of unique 3-DTA heterodimers, formed via intermolecular ketalization between talaroconvolutin-type 3-DTAs and a C₁₀ polyketide. Compound <b>5</b> is the first nor-talaroconvolutin-type 3-DTA with the reduction of the <i>para</i>-hydroxybenzyl, while <b>6</b> contains a unique epoxy ring system, unprecedented in 3-DTAs. We discovered for the first time that compounds <b>6</b> and <b>7</b> exhibit inhibitory activity against RSL3-induced ferroptosis. Notably, <b>6</b> exhibited potent ferroptosis inhibition with an EC₅₀ value of 7.77 μM. Mechanistic investigations indicate that <b>6</b> suppresses ferroptosis by alleviating lipid peroxidation and upregulating NRF2 expression. The present work provides new insights into the structural diversity and pharmaceutical potential of 3-DTAs.