Iron metabolism and ferroptosis: druggable targets to delay the progression of lupus nephritis.

Lupus nephritis (LN) is the renal manifestation of the autoimmune disease systemic lupus erythematosus (SLE). LN is characterized by a dysregulated immune system, the presence of autoantibodies, and renal immune complex deposits, which collectively injure the kidney. However, novel nonimmune pathogenic mechanisms of human LN are continuously uncovered, presenting new challenges as well as opportunities for intervention. Iron accumulation and ferroptosis in the glomerular structure and renal tubules are relatively newly identified pathological features in LN. Ferroptosis is an iron-dependent nonapoptotic form of regulated cell death. Unlike generic oxidative stress mechanisms, ferroptosis occurs when the cellular antioxidative mechanism cannot suppress the oxidation of the cell membrane eventually leading to cell membrane rupture. Since iron absorption and recycling occur in the renal tubules, the renal tissue is particularly susceptible to ferroptosis. Ferroptosis inhibitors that reduce toxic phospholipid hydroperoxides to their corresponding nontoxic alcohols, or trap radicals in phospholipid bilayers, have improved disease outcomes in murine models of SLE/LN. In this review, we discuss mechanisms by which iron accumulation and ferroptosis perpetuate pathology in LN. These studies suggest that ferroptosis is very likely integral to parenchymal cell dysfunction in LN and a novel therapeutic target. The goal of this review is to introduce the fundamentals of iron biology and ferroptosis to clinicians and basic scientists and spur research to identify intracellular proferroptotic enzymes and their protein conjugates as potential targets to improve LN.