Colorectal cancer (CRC) remains one of the leading causes of cancer‑related mortality worldwide. Despite advances in targeted therapies, drug resistance and limited efficacy in KRAS‑mutant CRC continue to present clinical challenges. Antrodia cinnamomea, a medicinal fungus, demonstrates antitumor properties; however, the mechanisms of its triterpenoid compound, 4‑acetylantrocamol LT3 (LT4), remain unclear. The present study investigated the effects of LT4 on KRAS‑mutant HCT116 CRC cells using cell viability, colony formation and migration assays. Western blotting was also employed to examine key signaling pathways. Transcriptome profiling via RNA sequencing was followed by Kyoto Encyclopedia of Genes and Genomes/Gene Ontology enrichment and protein‑protein interaction network analyses using STRING, CytoHubba and Molecular Complex Detection (MCODE). Molecular docking with PI3Kγ (PDB: 1E7U) was conducted to evaluate the predicted binding position and docking energy of LT4. The results indicated that LT4 significantly inhibited HCT116 cell proliferation and migration, induced a mesenchymal‑to‑epithelial transition, suppressed PI3K/AKT/mTOR and ERK signaling and activated the GSK3β/FOXO and phosphorylated‑p38/p21 axes. LT4 also reduced the levels of cyclooxygenase‑2 and anti‑apoptotic proteins (Bcl‑2 and Bcl‑XL) and reduced the expression of the mitochondrial respiratory chain protein cytochrome c oxidase subunit IV. Transcriptomic analysis identified the PI3K/AKT pathway as the most significantly enriched signaling cascade. Network topology analyses highlighted solute carrier family 3 member 2, Cyclin D1, phosphoserine aminotransferase 1 and ChaC glutathione‑specific γ‑glutamylcyclotransferase 1 as central nodes, linking the effects of LT4 to nutrient signaling, redox homeostasis and serine metabolism. Molecular docking confirmed that LT4 stably occupied the ATP‑binding pocket of PI3Kγ with a binding energy comparable to wortmannin and a conformation similar to antroquinonol. In conclusion, to the best of our knowledge, the present study is the first to comprehensively demonstrate the multi‑target anti‑CRC effects of LT4, highlighting its potential as a therapeutic agent, especially in KRAS‑mutant CRC.
Lin et al. (Fri,) studied this question.