HMGB1 regulates erastin-induced ferroptosis via RAS-JNK/p38 signaling in HL-60/NRASQ61L cells.

Ferroptosis is emerging as a new form of regulated cell death driven by oxidative injury promoting lipid peroxidation in an iron-dependent manner. High mobility group box 1 (HMGB1) plays an important role in leukemia pathogenesis and chemotherapy resistance. The mechanisms of ferroptosis in tumor pathogenesis and treatment have been a recent research focus but the role of HMGB1 in regulating ferroptosis especially in leukemia still remains largely unknown. Here, we shown that HMGB1 is a critical regulator of eratin-induced ferroptosis in HL-60 cell line expressing NRASQ61L (HL-60/NRASQ61L). Erastin enhanced ROS levels, thereby promoting cytosolic translocation of HMGB1 and enhancing cell death. Knockdown of HMGB1 decreased erastin-induced ROS generation and cell death in an iron-mediated lysosomal pathway in HL-60/NRASQ61L cells. Knockdown of HMGB1 or rat sarcoma (RAS), or pharmacological inhibition of JNK and p38 decreased TfR1 levels in HL-60/NRASQ61L cells. Importantly, these data were further supported by our in vivo experiment, in which xenografts formed by HMGB1 knockdown HL-60/NRASQ61L cells had lower PTGS2 and TfR1 expression than that in control mice. Taken together, these results suggest that HMGB1 is a novel regulator of ferroptosis via the RAS-JNK/p38 pathway and a potential drug target for therapeutic interventions in leukemia.