**4. Conclusions**

In summary, the utilization of the OSMAC (one strain many compounds) culture strategy effectively modified the chemical profile of the Arctic-derived fungus *Eutypella* sp. D-1 when cultivated in different media. This approach resulted in the production of five cytosporin polyketides (compounds **1**–**3** and **11**–**12**) from a rice medium and eight cytosporins (compounds **2** and **4**–**11**) from a solid defined medium. Remarkably, compound **1** contained a unique skeleton formed by the ester linkage of two moieties: cytosporin F (**12**) and the eudesmane-type sesquiterpene dihydroalanto glycol. Compounds **6** and **7**, characterized by a cyclic carbonate-fused cytosporin skeleton, were found to be rare in nature. However, these metabolites only exhibited weak immunosuppressive inhibitory activity against ConA-induced T cell proliferation in the antimicrobial, cytotoxic, and immunosuppressive evaluation. Collectively, this work showcased that changing the fermentation medium could be an effective strategy to trigger the production of secondary metabolites from fungi derived from the polar extreme environment.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/article/ 10.3390/md21070382/s1, 1D and 2D NMR, UV, IR, and HRESMS data of **1**–**7**.

**Author Contributions:** H.-B.Y. designed this study and drafted the work. H.-B.Y. and Z.N. performed the collection, extraction, isolation, and structure elucidation. Y.-P.Z. and B.H. performed the bioactive evaluation. Y.H. contributed to checking the isolation process. X.-L.L. checked the structure elucidation process. B.-H.J. and X.-Y.L. supervised the laboratory work and contributed to the critical proofreading and revision of the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was financially supported by the National Key Research and Development Project (Nos. 2022YFC2804500 and 2022YFC2804105), the Natural Science Foundation of Shanghai (No.20ZR1470600), and Shanghai Pujiang Program (No.2020PJD082).

**Institutional Review Board Statement:** Not applicable.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author.

**Conflicts of Interest:** The authors declare no conflict of interest.
