Sulfasalazine promotes ferroptosis through AKT-ERK1/2 and P53-SLC7A11 in rheumatoid arthritis

Abstract

Objective Ferroptosis has been reported to play a role in rheumatoid arthritis (RA). Sulfasalazine, a common clinical treatment for ankylosing spondylitis, also exerts pathological influence on the progression of rheumatoid arthritis including the induced ferroptosis of fibroblast-like synoviocytes (FLSs), which result in the perturbated downstream signaling and the development of RA. The aim of this study was to investigate the underlying mechanism so as to provide novel insight for the treatment of RA. Methods CCK-8 and Western blotting were used to assess the effect of sulfasalazine on FLSs. A collagen-induced arthritis mouse model was constructed by the injection of collagen and Freund’s adjuvant, and then, mice were treated with sulfasalazine from day 21 after modeling. The synovium was extracted and ferroptosis was assessed by Western blotting and immunofluorescence staining. Results The results revealed that sulfasalazine promotes ferroptosis. Compared with the control group, the expression levels of ferroptosis-related proteins such as glutathione peroxidase 4, ferritin heavy chain 1, and solute carrier family 7, member 11 (SLC7A11) were lower in the experimental group. Furthermore, deferoxamine inhibited ferroptosis induced by sulfasalazine. Sulfasalazine-promoted ferroptosis was related to a decrease in ERK1/2 and the increase of P53. Conclusions Sulfasalazine promoted ferroptosis of FLSs in rheumatoid arthritis, and the PI3K-AKT-ERK1/2 pathway and P53-SLC7A11 pathway play an important role in this process.

Ferroptosis in Cancer Therapy: Mechanisms, Small Molecule Inducers, and Novel Approaches

“… 53 The p53 can transcriptionally repress SLC7A11 expression at the transcriptional level, thereby promoting the occurrence of ferroptosis in cells. 54 Also, p53 releases Arachidonate 12-lipoxygenase (ALOX12). Free ALOX12 oxidizes cell membrane phospholipids’ polyunsaturated fatty acid chains, leading to ferroptosis.…”

“… 156 It is a potent inhibitor of system Xc − that characteristically inhibits cystine transport mediated by SLC7A11. 54 SAS can effectively induce ferroptosis in tumor cells such as Multiple myeloma (MM) cells, 157 Esophageal cancer (EC) cells 63 and TNBC cells. 158 Sorafenib is a protein kinase inhibitor approved for the treatment of hepatocellular carcinoma and advanced renal cell carcinoma.…”

Ferroptosis and endoplasmic reticulum stress in rheumatoid arthritis

“…Additionally, the active peptide G1dP3 promotes RA-FLS ferroptosis through a p53/SLC7A11 axis-dependent mechanism ( 53 ). Sulfasalazine, an important biological agent, was found to inhibit System Xc- ( 54 ). Beyond the classical ferroptosis antioxidant pathways, the CoQ10 pathway, which is unrelated to GPX4, was found to act as a ROS scavenger and anti-inflammatory substance.…”

Effect of sulfasalazine on ferroptosis during intestinal injury in rats after liver transplantation

“…Studies have shown that ferroptosis in intestinal epithelial cells is involved in the pathophysiological mechanism of intestinal I/R injury 8 , 9 . In addition, some studies have found that SAS not only inhibits the NF-κB pathway, but also inhibits the ferroptosis signal pathway System Xc — 10 , 11 . The aim of this study was to evaluate the role of ferroptosis in perioperative LT intestinal injury in rats and further clarify the possible mechanism of the ferroptosis activator sulfasalazine (SAS) in perioperative LT-induced intestinal injury in rats.…”