Liproxstatin-1 induces cell cycle arrest, apoptosis, and caspase-3/GSDME-dependent secondary pyroptosis in K562 cells

Leukemia is a fatal hematopoietic disorder with a poor prognosis. Drug resistance is inevitable after the long-term use of chemotherapeutic agents. Liproxstatin-1, commonly known as a ferroptosis inhibitor, has never been reported to have anticancer effects. In the present study, the antileukemic role of liproxstatin-1 in K562 leukemia cells was investigated. Liproxstatin-1 inhibited K562 cell proliferation in a doseand time-dependent manner. RNA sequencing revealed several pathways that were affected by liproxstatin-1, such as the G1/S transition of the mitotic cell cycle and extrinsic or intrinsic apoptotic signaling pathways. The results of flow cytometry indicated that liproxstatin-1 arrests the cell cycle at the G1 phase, and even at the G2/M phase. p21(WAF1/CIP1), a cyclin-dependent kinase inhibitor, was upregulated. It was also determined that liproxstatin-1 induced BAX and TNF-alpha expression, which was accompanied by cleavage of caspase-3 and PARP. The caspase-3-specific inhibitor z-DEVD-FMK rescued some of the apoptotic cells. Interestingly, K562 cells were characterized by swelling and plasma membrane rupture when treated with a high concentration of liproxstatin-1, which was inconsistent with the typical apoptotic appearance. Thus, it was hypothesized that apoptosis-mediated pyroptosis occurs during liproxstatin-1-induced cell death. The expression of the hallmark of pyroptosis, the cleaved N-terminal GSDME, increased. Additionally, it was observed that endoplasmic reticulum stress and autophagy were involved in liproxstatin-1-induced cell death. Collectively, liproxstatin-1 induced cell cycle arrest, apoptosis, and caspase-3/GSDME-dependent secondary pyroptosis in K562 leukemia cells, which provides new hope for the treatment of leukemia.

Automated summary

The study found that Liproxstatin-1 inhibited the proliferation of K562 leukemia cells and exerted anticancer effects by affecting the cell cycle and apoptotic signaling pathways. Liproxstatin-1 induced cell cycle arrest, apoptosis, and pyroptosis, providing new hope for leukemia treatment.