PPIA as a central regulator in a novel cell death pathway activated by iron homeostasis and redox disruption in multiple myeloma

Abstract

Multiple myeloma (MM) patients frequently experience relapse, disease progression, and drug resistance, necessitating novel therapeutic strategies. This study investigates the role of peptidylprolyl isomerase A (PPIA) in mediating dihydroartemisinin (DHA)-induced ferroptosis in MM. Building on our previous work establishing the prognostic relevance of ferroptosis in MM, we elucidate the mechanism by which DHA triggers this form of cell death through the disruption of iron metabolism and redox homeostasis. DHA significantly reduces the viability of MM cell lines and primary CD138+ cells derived from patient bone marrow samples and attenuates tumor burden in orthotopic MM models. Mechanistically, DHA upregulates the iron-regulatory genes transferrin receptor 1 (TFRC) and heme oxygenase-1 (HMOX1), thereby perturbing iron homeostasis and promoting ferroptosis. Crucially, DHA targets the oxidized form of PPIA, a redox-sensitive chaperone, binding to it and preventing its reduction, which elevates intracellular reactive oxygen species (ROS). Combined treatment with DHA and erastin, which concurrently disrupt iron and amino acid metabolism, exerts synergistic cytotoxicity and enhances MM inhibition. Furthermore, in a syngeneic mouse model, DHA promotes T-cell activation and augments tumor suppression. Collectively, these findings underscore PPIA's pivotal role in a novel ferroptotic cell death pathway and reveal new therapeutic opportunities for MM.

1. Introduction

Multiple myeloma (MM) is a hematologic malignancy characterized by clonal accumulation of malignant plasma cells within the bone marrow. Although recent therapeutic advances—such as immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies—have improved patient outcomes, MM remains largely incurable due to frequent relapse and the emergence of drug resistance, underscoring the urgent need for novel treatment strategies [1].

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation and is primarily triggered by disturbances in iron homeostasis and cellular redox balance [2]. Iron overload enhances reactive oxygen species (ROS) production via Fenton chemistry, promoting lipid peroxidation and ferroptotic cell death [3]. Modulation of iron-handling proteins influences ferroptotic susceptibility; for example, knockdown of transferrin receptor 1 (TFRC) reduces ferroptosis, whereas upregulation of heme oxygenase-1 (HMOX1) can increase ferroptotic sensitivity by elevating intracellular labile iron [4,5]. In parallel, the antioxidant defense system—centered on glutathione peroxidase 4 (GPX4) and the cystine/glutamate antiporter system xc–—scavenges lipid hydroperoxides and thus prevents ferroptosis; disruption of this defense permits toxic accumulation of lipid peroxides and triggers ferroptotic death [6,7].