Periconoid A, a Novel Ergosterol Derivative from Periconia caespitosa, Induces Apoptosis in Nasopharyngeal Carcinoma Cells Accompanied by the Enrichment of Inflammatory Pathways

Chemical investigation of marine Conus Literatus endophytic fungus Periconia caespitosa HDYXY-1 led to the isolation and characterization of seven novel compounds, including an oxirane-fused cyclohexanone (1), benzothiazole isomers (2 and 3), rare cyano-bearing phenyl ethers (4 and 5), as well as ergosterol derivatives (8 and 9), along with three known analogs (6, 7, and 10). Their structures were elucidated via NMR, HRESIMS, HRAPCIMS, X-ray diffraction, and ECD/DP4+ calculations. Among them, the ergosterol derivative Periconoid A (8) showed potent cytotoxicity against glioblastoma (LN-229, IC50 = 10.05 μM) and nasopharyngeal carcinoma (NPC; CNE2, IC50 = 5.62 μM) cells. Mechanism studies revealed that Periconoid A (8) triggers mitochondria-dependent apoptosis by modulating the Bax/Bcl-2 ratio, activating caspase-3, and inducing PARP-1 cleavage. Transcriptomic analysis indicated that 8 enriches inflammatory response pathways (TNF, JAK-STAT, and NF‑κB), suggesting an inflammation-associated apoptotic mechanism. Molecular docking confirmed a high binding affinity of Periconoid A (8) for the Bcl‑2 protein (–7.6 kcal/mol) through a dual‑polar anchoring network. ADME prediction indicated favorable druggability with high GI absorption and a PAINS‑free profile. Collectively, these findings establish Periconoid A (8) as a promising lead candidate for anti‑NPC drug development, acting through a mechanism that activates inflammation-associated apoptosis.