Schisandrin B exhibits anti‑proliferative effects by inducing ferroptosis in pancreatic cancer

Pancreatic Cancer (PC) is a lethal malignant tumor of the digestive system with a low survival rate. Current therapies provide only modest benefits for patients and new therapeutic options are urgently needed. Schisandrin B (Sch B) has demonstrated novel antitumor activity in several preclinical models; however, its effects on PC remain unclear. In the present study, the anti‑proliferative effects of Sch B in vitro were evaluated in PC cell lines. The underlying molecular mechanisms were explored using RNA Sequencing, drug affinity responsive target stability (DARTS), molecular docking and small interfering RNA transfection. The antitumor effects of Sch B in vivo were evaluated using both a subcutaneous xenograft mouse model and an orthotopic genetically engineered mouse model. The in vitro studies showed that Sch B significantly inhibited the proliferation of PC cells and induced cell death in a dose‑dependent manner. Mechanistically, transcriptome Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that differentially expressed genes were significantly enriched in the 'ferroptosis' signaling pathway. Sch B triggered Ferroptosis by promoting iron overload, lipid peroxidation and glutathione (GSH) depletion, as well as regulating the expression of ferroptosis‑related proteins [including GSH peroxidase 4, solute carrier family 3 member 2, acyl‑CoA synthetase long‑chain family member 4 (ACSL4), γ‑glutamyl‑cysteine Ligase catalytic subunit and GSH synthetase]. Furthermore, pre‑treatment with the Ferroptosis inhibitor ferrostatin‑1 partially reversed the anti‑proliferative effects and ferroptosis‑related events induced by Sch B. DARTS assays and molecular docking analyses confirmed the direct interaction between Sch B and ACSL4. Notably, silencing ACSL4 expression also partially reversed the anti‑proliferative effects and ferroptosis‑related events induced by Sch B. The in vivo studies demonstrated that Sch B suppressed tumor growth in subcutaneous xenograft models with good biosafety, and inhibited metastasis in orthotopic genetically engineered mice. In conclusion, Sch B may exert anti‑proliferative effects at least partially by inducing ACSL4‑dependent Ferroptosis in PC.