Saikosaponin A Inhibits Migration/Invasion and Triggers Cell‐Cycle Arrest and Autophagy‐Induced Cell Death in HCT116 Cells and In Vivo

ABSTRACT Colorectal cancer (CRC) is a major cause of cancer‐related mortality, and current therapies are often limited by severe adverse effects and high recurrence rates. Natural products with multi‐target activity and low toxicity offer promising therapeutic alternatives. Saikosaponin A (SSA), a triterpenoid saponin isolated from Radix Bupleuri , has shown antitumor potential, but its role and mechanisms in CRC remain unclear. This study aimed to evaluate the antitumor effects of SSA in CRC and to elucidate its underlying molecular mechanisms. SSA significantly inhibited HCT116 cell viability while exhibiting low toxicity toward normal HEK293 cells. SSA induced pronounced morphological changes and cell cycle arrest. Mechanistic investigations revealed that SSA inhibited the mTOR signaling pathway, thereby promoting autophagy, as evidenced by increased LC3B‐II/I ratios and enhanced autophagolysosome formation. In addition, SSA suppressed cell migration and metastatic potential through inhibition of the PI3K/AKT signaling pathway. Notably, SSA‐induced autophagy was closely associated with its anti‐metastatic effects. In vivo, SSA treatment (5 mg/kg) markedly suppressed tumor growth in HCT116 xenograft mice without causing detectable systemic toxicity. SSA exhibits potent antitumor activity against CRC by inducing autophagy and inhibiting metastasis‐related signaling pathways, supporting its potential as a low‐toxicity natural therapeutic candidate for CRC.