Erianin inhibits tumor growth by promoting ferroptosis and inhibiting invasion in hepatocellular carcinoma through the JAK2/STAT3/SLC7A11 pathway

Abstract

Iron has been found to be involved in the tumor cell proliferation process, which can lead to the increased sensitivity of cancer cells to ferroptosis. Since erianin is associated with oxidative stress in hepatocellular carcinoma (HCC), we hypothesized that the therapeutic effect and mechanism of erianin on HCC is related to ferroptosis. HCC cells were stimulated with increase of erianin concentrations for 24 h, and the survival rates of Huh‐7 and HepG2 cells gradually decreased. After intervention with different doses of erianin, cell proliferation, clone number, and invasion were prominently decreased, apoptosis ratio was increased. Moreover, Nec‐1, CQ, and Z‐VAD had no effect on the cell viability induced by erianin, while the combination of ferroptosis inhibitors (deferoxamine mesylate, ferrostatin‐1, and liproxstatin‐1) and erianin prominently increased cell survival rate. Erianin pretreatment induced ferroptosis by enhancing reactive oxygen species, MDA, and Fe2+ levels, and reducing GSH levels. Erianin activated JAK2/STAT3 pathway and inhibited SLC7A11 and GPX4 expression, thereby inducing ferroptosis. Besides, tumor growth was significantly inhibited in the erianin‐treated mice, and there was no obvious toxicity in the mice. Erianin reduced proliferation and invasion of HCC cells by inducing ferroptosis by blocking the JAK2/STAT3/SLC7A11 pathway, thereby impeding tumor growth.