PEITC restores chemosensitivity in cisplatin-resistant non-small cell lung cancer by targeting c-Myc/miR-424-5p.

We aimed to investigate the potential of phenethyl isothiocyanate (PEITC) as an effective therapeutic agent in overcoming cisplatin resistance in non-small cell lung cancer (NSCLC). Cell viability was measured using the CCK-8 assay and flow cytometry, and a xenograft model was established to verify the antitumor effect of PEITC on A549/DDP cells. The JASPAR database was used to predict the potential molecular mechanisms. Mechanistic exploration was conducted using Western blot and qRT-PCR analyses, and predictions were validated with a dual-luciferase reporter assay. The findings show that PEITC treatment led to decreased cell proliferation, increased apoptosis, and cessation of cell cycle progression at G1 phase. PEITC inhibited tumor growth in a concentration-dependent manner in a mouse xenograft model. Examination of the possible mechanism of PEITC showed that this compound led to down-regulation of miR-424-5p and c-Myc, up-regulation of suppressor of cytokine signaling 5/6 (SOCS5/6), and down-regulation of AKT/PI3K/mTOR signaling. A dual-luciferase reporter assay showed that miR-424-5p targeted c-Myc, and that silencing of c-Myc decreased the expression of downstream genes. These results suggest that PEITC inhibited the growth and increased the sensitivity of cisplatin-resistant NSCLC cells by targeting c-Myc and down-regulating the PI3K/AKT/mTOR pathway. Clinical trial number: not applicable. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12672-025-03824-1.