Endoplasmic reticulum oxidoreductase 1 alpha (ERO1A) and Ribosyldihydronicotinamide dehydrogenase [quinone] (NQO2) (ERO1A/NQO2)

ERO1A (Endoplasmic Reticulum Oxidoreductase 1 Alpha) and NQO2 (Ribosyldihydronicotinamide Dehydrogenase [Quinone]) are distinct enzymes that have recently been characterized as a dual-target axis for the small-molecule inhibitor rigosertib [1, 6]. ERO1A is an essential ER-resident oxidoreductase that facilitates disulfide bond formation in nascent proteins by oxidizing protein disulfide isomerase (PDI), a process that generates hydrogen peroxide as a byproduct [8, 10]. NQO2 is a cytosolic flavoprotein that acts as a redox sensor and quinone reductase, utilizing non-canonical cofactors like nicotinamide riboside (NRH) [5, 11]. In the context of cancer therapy, the simultaneous engagement of ERO1A and NQO2 by drugs like rigosertib triggers a surge in reactive oxygen species (ROS), which activates the c-Jun N-terminal kinase (JNK) pathway and inhibits RAS-MAPK signaling [1, 9]. This dual-targeting mechanism also promotes NLRP3-dependent inflammatory responses and immunogenic cell death, potentially reprogramming the tumor microenvironment to enhance the efficacy of immune checkpoint inhibitors [1, 4]. While ERO1A is frequently upregulated in aggressive, hypoxic tumors and linked to poor prognosis, NQO2 is a well-known off-target for various kinase inhibitors, making this specific interaction a critical focus for understanding drug efficacy and safety [7, 11].

Other names

ERO1LERO1-alphaERO1-like protein alphaQuinone reductase 2QR2NRH:quinone oxidoreductase 2Ribosyldihydronicotinamide dehydrogenase [quinone]

Rigosertib binds to ERO1A and NQO2 to induce ROS-dependent JNK activation and NLRP3-mediated inflammatory responses, leading to RAS-MAPK pathway inhibition and immunogenic cell death [1, 6, 9].