D‑salicin induces oxidative stress‑mediated ERK1/2 suppression and apoptosis in endometrial cancer cells

Endometrial cancer is a common gynecologic malignancy for which therapeutic options remain limited in advanced or treatment‑resistant disease. Natural compounds that selectively perturb cancer‑associated redox signaling and survival pathways may offer novel anticancer strategies. The present study investigated the anticancer effects of D‑salicin in the endometrial adenocarcinoma‑derived Ishikawa cell line, with a focus on oxidative stress and extracellular signal‑regulated kinase (ERK)1/2 signaling, and assessed cancer selectivity using normal human dermal fibroblasts (HDF). D‑salicin selectively reduced Ishikawa cell viability in a concentration‑dependent manner while largely sparing HDF. This cytotoxic effect was accompanied by marked intracellular reactive oxygen species (ROS) accumulation, increased lipid peroxidation (MDA) and depletion of total glutathione (GSH), indicating induction of oxidative stress. Elevated oxidative burden was associated with caspase‑3 activation and concentration‑dependent suppression of ERK1/2 phosphorylation, both of which were attenuated by N‑acetylcysteine (NAC) co‑treatment. To determine redox dependence, NAC was incorporated as an antioxidant co‑treatment. D‑salicin induced a significant, concentration‑dependent reduction in Ishikawa cell viability (P<0.0001), whereas HDF viability remained largely preserved across the tested range (P>0.05). In Ishikawa cells, D‑salicin markedly increased intracellular ROS in a dose‑dependent manner (P≤0.01) and this effect was markedly attenuated by NAC co‑treatment (P≤0.01), indicating an NAC‑sensitive oxidative component. Consistent with redox disruption, D‑salicin increased MDA levels and depleted total GSH in Ishikawa cells (P≤0.01). Elevated oxidative stress was accompanied by increased caspase‑3 levels (P≤0.01), supporting engagement of apoptotic signaling. Moreover, D‑salicin markedly suppressed ERK1/2 phosphorylation in Ishikawa cells (P<0.0001), while ERK signaling was not markedly altered in HDF cells (P>0.05). Notably, NAC co‑treatment partly restored p‑ERK1/2 levels under the IC₅₀ condition (P<0.01 vs. D‑salicin alone), supporting a redox‑linked contribution to ERK pathway modulation. Collectively, these findings indicated that D‑salicin exerts selective anticancer effects in endometrial cancer cells by inducing oxidative stress and disrupting ERK1/2‑mediated survival signaling, with NAC‑sensitive modulation consistent with involvement of a redox‑responsive ROS‑ERK axis.