Qizhu Jianwei decoction triggers ferroptosis by exosome-mediated miR-199-3p/ACSL4 signaling pathways

Qizhu Jianwei decoction (QZJWD) is a conventional Chinese medicine formulation used to treat gastric cancer, however, its association with GC and ferroptosis remains poorly understood.

Our research endeavors centered around investigating the potential molecular mechanism of QZJWD in suppressing GC.

A UHPLC-QTOF-MS technique was utilized for determining the major constituents of QZJWD. Laboratory-based experiments such as CCK8, wound healing, transwell invasion assay, and WB were conducted to examine QZJWD's role in influencing HGC-27 and AGS cells, Fe²⁺, ROS, MDA and GPx levels were assayed to evaluate the activation of ferroptosis. The subcutaneous tumor tissues in nude mice injected with QZJWD were examined. NTA, TEM, and WB served to validate exosomes. To identify the modified miRNAs involved in GC and ferroptosis, sRNA-seq analysis was utilized. Luciferase reporter assay and miRNA mimics transfection experiment were further used validate the specific binding of miRNA and the effect of QZJWD.

QZJWD treatment markedly suppressed the proliferation, migration, and invasion of gastric cancer cells. QZJWD effectively promoted ferroptosis both in vitro and in vivo, by elevating levels of Fe²⁺, MDA, ROS, and ACSL4 while downregulating GPx levels. Additionally, exosomes originating from QZJWD-treated gastric carcinoma cells were internalized by other gastric carcinoma cells, further amplifying ferroptosis. Notably, QZJWD downregulated exosomal-miR-199-3p, which facilitated ferroptosis in gastric tumor cells through directly targeting ACSL4.

QZJWD may induce ferroptosis through the exosome-mediated miR-199-3p/ACSL4 signaling pathway in gastric cancer. Our research identifies a promising approach for addressing GC in clinical settings.