Colorectal cancer (CRC) ranks as the third most prevalent malignancy worldwide, and effective treatment options remain limited. Perillaldehyde (PAH), a key bioactive component derived from Perilla, has shown promise in managing CRC, yet its underlying mechanisms are not fully understood. This work investigates the anti-CRC potential of PAH and elucidates its mode of action, aiming to support its development as a candidate therapeutic agent. For the in vitro portion, we employed CCK-8 assays, colony formation tests, EdU incorporation, flow cytometry, and Western blot analyses to examine how PAH influences CRC cell growth and apoptosis. For in vivo evaluation, we created a subcutaneous xenograft mouse model to determine PAH’s antitumor effects. Transcriptome sequencing was conducted to uncover possible mechanisms—particularly those related to autophagy—and these findings were further confirmed by TEM, immunofluorescence, Western blotting, and inhibitor-based experiments. SRD5A1 was identified through Swiss Target Prediction as a likely target and validated via molecular docking, molecular dynamics simulations, and CETSA. Subsequent bioinformatics analyses explored the clinical importance and functional relevance of SRD5A1, and a selective inhibitor was used for experimental confirmation.
PAH displayed notable anti-CRC activity in both cellular and animal models. RNA-seq results, supported by follow-up experiments, indicate that PAH may suppress CRC by activating autophagy through modulation of the PI3K/AKT pathway. Computational and experimental data suggest SRD5A1 as a potential PAH target, where PAH treatment reduces SRD5A1 expression and enhances autophagic signaling via PI3K/AKT inhibition. PAH appears to exert its anti-CRC effects partly by interacting with SRD5A1, subsequently promoting autophagy through suppression of the PI3K/AKT pathway. These findings offer new insights into possible diagnostic and therapeutic approaches for CRC.
