Promiscuous enzyme SQOR in cellular metabolism and ferroptosis regulation

Abstract

Ferroptosis, an iron-dependent form of programmed cell death, is primarily driven by the accumulation of lipid peroxides through radical generation, notably via the Fenton reaction. Emerging evidence highlights the intricate link between ferroptosis and cellular metabolism, with metabolic enzymes playing pivotal roles in its regulation. Sulfide quinone oxidoreductase (SQOR), traditionally recognized for its role in hydrogen sulfide (H2S) detoxification and electron transport chain (ETC) activation, has recently been identified as a promiscuous enzyme with a novel function in ferroptosis regulation. This review explores SQOR's canonical function in H2S metabolism and its emerging role in ferroptosis resistance through the production of ubiquinol and hydropersulfides, radical-trapping antioxidants. Additionally, we provide insights into potential future research directions, emphasizing SQOR's therapeutic relevance in ferroptosis-associated diseases. [BMB Reports 2025; 58(6): 233-237].

Fig. 1

Canonical roles of SQOR in sulfur metabolism. SQOR catalyzes the oxidation of hydrogen sulfide to sulfane sulfur. Simultaneously, the released electrons are transferred to ubiquinone, which is subsequently reduced to ubiquinol. GSH or sulfite serves as sulfur acceptors, and the GSSH or thiosulfate generated by SQOR undergoes further processing by other serial metabolic enzymes, initiating the sulfur oxidation pathway. The reduced ubiquinol donates electrons to complex III of the ETC, thereby contributing to mitochondrial energy production.

Fig. 2

Novel role of SQOR in the regulation of ferroptosis. SQOR is capable of processing both hydrogen sulfide and hydrogen selenide as substrates. SQOR transfers electrons from hydrogen sulfide or hydrogen selenide to ubiquinone, reducing it to ubiquinol. During this process, GSH or sulfite acts as an elemental sulfur acceptor, leading to the formation of GSSH or thiosulfate, respectively. The reduced ubiquinol not only promotes the mitochondrial ETC by donating electrons to complex III but also plays a critical role in inhibiting ferroptosis by trapping lipid radicals. Interestingly, hydropersulfides such as GSSH, generated by SQOR-mediated sulfide oxidation, exhibit strong radical-trapping activity, thereby inhibiting lipid peroxidation and ferroptosis. Overall, SQOR is emerging as a key regulator of ferroptosis.