Cyclodepsipeptides and Fatty Acid Lactones from the Freshwater-Derived Fungus, <i>Talaromyces gwangjuensis</i>, and Their Potential as Autophagy Activators

Autophagy is a primary cellular mechanism that entails the degradation and recycling of impaired or redundant cellular constituents. It plays an essential role in maintaining cellular health and homeostasis. Dysfunction in autophagy has been implicated in a wide range of diseases, including cancer, cardiovascular diseases, and neurodegenerative diseases. A total of 200 fungal extracts were screened for their ability to modulate autophagy in HEK293A cells, a human kidney cell line stably expressing GFP-tagged LC3, a marker of autophagy. A potential autophagy regulator extract was identified from the freshwater-derived fungus, <i>Talaromyces gwangjuensis</i>. Through the implementation of Feature-Based Molecular Networking (FBMN), seven cyclodepsipeptides (<b>1</b>-<b>7</b>) and four lactone derivatives (<b>8</b>-<b>11</b>) were isolated from the bioactive fractions. The chemical structure of the newly isolated compounds, arthrichitins E-H (<b>1</b>-<b>4</b>) and gwangjupones A-D (<b>8</b>-<b>11</b>), were elucidated using 1D and 2D NMR spectroscopy, Marfey's analysis, <i>J</i>-based configuration analysis, ECD, and DP4+ probability calculations. Compounds <b>1</b>, <b>4</b>, and <b>6</b> were found to stimulate autophagic flux in IMR90 cells infected with an adeno-associated virus carrying an mCherry-GFP-LC3 construct, highlighting their potential as autophagy activators.