Targeting the ROS-JNK/p38 Axis: Schisandrin A as a Novel Therapeutic Candidate for Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a highly lethal malignancy with limited therapeutic options. Schisandrin A (Sch A), a bioactive lignan, demonstrates anti-cancer potential, but its effectiveness against ESCC has yet to be investigated. Human ESCC cell lines (KYSE30 and KYSE510) and normal HEKa cells were treated with Sch A at concentrations ranging from 10 to 80 μM. We assessed cell viability, colony formation, apoptosis, ROS production, mitochondrial membrane potential, and cell cycle distribution. The expression of proteins involved in JNK/p38 MAPK signaling, Bcl-2 family members, and cell cycle regulators was analyzed using Western blotting. Specific inhibitors (SP600125, SB203580, NAC, Z-vad-fmk) were employed to validate the underlying mechanisms. Sch A reduced cell viability and colony formation in KYSE30 and KYSE510 cells in a dose-dependent manner while sparing normal HEKa cells. It induced apoptosis, G0/G1 phase arrest, ROS generation, and caspase activation. Notably, these effects were partially reversed by pathway-specific inhibitors. Sch A activated JNK/p38 MAPK signaling, downregulated Bcl-2 and Mcl-1, upregulated Bax and Bad, and modulated cell cycle regulators such as cyclin D1, CDK4/6, and p27. Sch A selectively induces apoptosis in ESCC cells through ROS-JNK/p38-mediated pathways, mitochondrial dysfunction, and cell cycle arrest. These findings indicate that Sch A is a promising therapeutic candidate for treating ESCC.