Drugs Repurposed as Antiferroptosis Agents Suppress Organ Damage, Including AKI, by Functioning as Lipid Peroxyl Radical Scavengers

Abstract

BackgroundFerroptosis, nonapoptotic cell death mediated by free radical reactions and driven by the oxidative degradation of lipids, is a therapeutic target because of its role in organ damage, including AKI. Ferroptosis-causing radicals that are targeted by ferroptosis suppressors have not been unequivocally identified. Because certain cytochrome P450 substrate drugs can prevent lipid peroxidation via obscure mechanisms, we evaluated their antiferroptotic potential and used them to identify ferroptosis-causing radicals.MethodsUsing a cell-based assay, we screened cytochrome P450 substrate compounds to identify drugs with antiferroptotic activity and investigated the underlying mechanism. To evaluate radical-scavenging activity, we used electron paramagnetic resonance–spin trapping methods and a fluorescence probe for lipid radicals, NBD-Pen, that we had developed. We then assessed the therapeutic potency of these drugs in mouse models of cisplatin-induced AKI and LPS/galactosamine-induced liver injury.ResultsWe identified various US Food and Drug Administration–approved drugs and hormones that have antiferroptotic properties, including rifampicin, promethazine, omeprazole, indole-3-carbinol, carvedilol, propranolol, estradiol, and thyroid hormones. The antiferroptotic drug effects were closely associated with the scavenging of lipid peroxyl radicals but not significantly related to interactions with other radicals. The elevated lipid peroxyl radical levels were associated with ferroptosis onset, and known ferroptosis suppressors, such as ferrostatin-1, also functioned as lipid peroxyl radical scavengers. The drugs exerted antiferroptotic activities in various cell types, including tubules, podocytes, and renal fibroblasts. Moreover, in mice, the drugs ameliorated AKI and liver injury, with suppression of tissue lipid peroxidation and decreased cell death.ConclusionsAlthough elevated lipid peroxyl radical levels can trigger ferroptosis onset, some drugs that scavenge lipid peroxyl radicals can help control ferroptosis-related disorders, including AKI.

Germ-Free Conditions Modulate Host Purine Metabolism, Exacerbating Adenine-Induced Kidney Damage

“…Tissues were fixed in 10% neutral buffered formalin and embedded in paraffin. Kidney sections were stained with Masson’s trichrome, and Sirius red [ 4 , 47 ]. For immunohistochemistry of F4/80, antigen retrieval from deparaffinized sections was performed using Target Retrieval Solution S1700 (Dako, Carpinteria, CA, USA) in an autoclave at 120 °C for five min.…”

Targeted inhibition of Rev‐erb‐α/β limits ferroptosis to ameliorate folic acid‐induced acute kidney injury

“…Based on a combination of luciferase reporter, EMSA and ChIP assays, we found that Rev‐erb‐α/β trans‐repress Slc7a11 and HO1 via direct binding to a RORE element, thereby promoting ferroptosis. Ferroptosis is also involved in the development of cisplatin‐, rhabdomyolysis‐ and ischaemia/reperfusion‐induced acute kidney injury in addition to folic acid‐induced acute kidney injury (Guerrero‐Hue et al, 2019; Hu et al, 2019; Mishima et al, 2020). It is tempting to propose that Rev‐erb‐α/β‐based therapeutic strategies are not restricted to folic acid‐induced acute kidney injury but are also applicable to other type of acute kidney injury as mentioned above.…”

The emerging role of ferroptosis in non-cancer liver diseases: hype or increasing hope?

“…Treatment with glycyrrhizin, a HMGB1 inhibitor, could alleviate the degree of liver damage by targeting ferroptosis via inhibition of oxidative stress. Another state-of-the-art study aimed to screen cytochrome P450 substrate compounds with antiferroptotic bioactivity 58 . Their results showed promethazine can ameliorate LPS/GalN-triggered acute liver failure via suppression of lipid peroxidation and decreased cell death.…”

“… Disease Ref. Model Compound/target Effect Mechanism/phenotype Acute liver failure 16 LPS/GalN-induced mice L02 cells Glycyrrhizin Inhibition of ferroptosis NRF2, HO-1, and GPx4↑ HMGB1↓ 58 LPS/GalN-induced mice Promethazine Inhibition of ferroptosis NA Acute liver injury 60 PHZ-induced mice/Ad-Sesn2 infected mice HepG2 cells Sestrin2 Inhibition of ferroptosis NRF2, TFR1, ferroportin↑ Alcoholic liver disease 15 SIRT1iKO mice Intestinal sirtuin1 (deficiency) Inhibition of ferroptosis Pro-inflammatory molecules LCN2, SAA1↓ Redox active iron–sulfur CISD1/2↓ 65 Lpin1 -Tg mice Adipose-specific lipin-1 (overexpression) Induction of ferroptosis Adiponectin-sirtuin1, adiponectin-FGF15 axis↓ NF-κB↑ NAFLD 74 CDE diet/MLKL −/− mice Trolox/DFO Inhibition of ferroptosis TNF-α, IL-1β, IL-6↓ Immune-mediated hepatitis 14 ConA-induced/Cav-1 −/− mice Caveolin-1 Inhibition of ferroptosis RNS, iNOS↓ 83 ConA-induced/IDO1 −/− mice IDO1 (deficiency) Inhibition of ferroptosis xCT↑ RNS↓ Ischemia/reperfusion injury 100 I/R mice Liproxstatin-1 Inhibition of ferroptosis MPO↓ 104 HID-fed I/R mice Ferrostatin-1/DFO/α-Tocopherol Inhibition of ferroptosis PTGS2↓ Inflammator...…”