A marine-derived meroterpenoid inhibits colorectal cancer via PI3K pathway modulation in mice.

Colorectal cancer is among the most leading cancers in China, characterized by activating mutations in PIK3CA or aberrant AKT signaling in approximately 30%-40% of cases. Marine natural products, especially those derived from marine fungi, offer a valuable source of novel phosphatidylinositol 3-kinase (PI3K) inhibitors. In this study, two novel phenylspirodrimane-type meroterpenoids, chloropenoids A and B (1 and 2), along with ten known analogues (3-12), were isolated from the marine-derived fungus Stachybotrys chlorohalonatus. The absolute configurations of 1 and 2 were established by time-dependent density functional theory electronic circular dichroism (TDDFT-ECD) calculations. Structural optimization via esterification at the C-2' position of 3 generated a series of derivatives (3a-3i), among which derivative 3a displayed potent antiproliferative activity against CT-26 colorectal cancer cells. Mechanistic studies revealed that 3a disrupted mitochondrial membrane potential, induced apoptosis (total apoptosis rate: approximately 32% at 12.50 μM), and induced G1-phase cell cycle arrest. Molecular docking and Western blot assays demonstrated that 3a effectively inhibited PI3K phosphorylation, consequently attenuating the PI3K/AKT/mTOR signaling cascade. In vivo evaluation using a BALB/c mouse xenograft model revealed that intraperitoneal administration of 3a (50 mg/kg/day for 10 days) significantly suppressed tumor growth (Tumor Growth Inhibition = 85.2%) compared with the control group, exhibiting superior efficacy and reduced systemic toxicity compared to the standard chemotherapy drug, 5-fluorouracil. These findings identify compound 3a as a promising candidate for further development as a PI3K inhibitor for colorectal cancer therapy and provide critical mechanistic insights into phenylspirodrimane-based antitumor agents. The online version contains supplementary material available at https://doi.org/10.1007/s42995-026-00356-7.