Hongkun Wu

Multiple myeloma (MM) is a refractory plasma cell neoplasm characterized by frequent development of drug resistance, leading to poor clinical outcomes. Activation of ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a promising cancer therapeutic strategy. In this study, we show that the circular RNA circ_0042819 exhibits high expression in both bone marrow and plasma samples from MM patients, with its overexpression strongly associated with disease progression and unfavorable prognosis. Mechanistically, circ_0042819 directly interacts with Up-frameshift protein 1 (UPF1) in MM cells, and the circ_0042819-UPF1 complex upregulates the expression of phospholipase A2 group VI (PLA2G6) via interacting with, and thus stabilizing, its mRNA. Furthermore, the circ_0042819-PLA2G6 axis suppresses ferroptosis through phospholipid remodeling in MM cells. Importantly, depletion of circ_0042819 or PLA2G6 enhances MM sensitivity to proteasome inhibitors (bortezomib and carfilzomib) by promoting ferroptosis both in vitro and in vivo. Collectively, our findings demonstrate that circ_0042819 is a potential non-invasive biomarker for the diagnosis and prognosis of MM, and that inhibition of the circ_0042819-PLA2G6 axis can mitigate the resistance of MM to proteasome inhibitors through ferroptosis sensitization, thus suggesting a novel therapeutic approach.

Extrahepatic cholangiocarcinoma (ECC), a highly malignant type of cancer with increasing incidence, has a poor prognosis due to limited treatment options. Based on genomic analysis of ECC patient samples, here we report that aldo-keto reductase family 1 member C1 (AKR1C1) is highly expressed in human ECC tissues and closely associated with ECC progression and poor prognosis. Intriguingly, we show that inducible AKR1C1 knockdown triggers ECC cells to undergo ferroptosis. Mechanistically, AKR1C1 degrades the protein stability of the cytochrome P450 family member CYP1B1, a newly discovered mediator of ferroptosis, via ubiquitin-proteasomal degradation. Additionally, AKR1C1 decreases CYP1B1 mRNA level through the transcriptional factor aryl-hydrocarbon receptor (AHR). Furthermore, the AKR1C1–CYP1B1 axis modulates ferroptosis in ECC cells via the cAMP–PKA signaling pathway. Finally, in a xenograft mouse model of ECC, AKR1C1 depletion sensitizes cancer cells to ferroptosis and synergizes with ferroptosis inducers to suppress tumor growth. Therefore, the AKR1C1–CYP1B1–cAMP signaling axis is a promising therapeutic target for ECC treatment, especially in combination with ferroptosis inducers.