Icariin enhances cell survival in lipopolysaccharide‑induced synoviocytes by suppressing ferroptosis via the Xc‑/GPX4 axis

Abstract

The mechanism of action of synovitis, as the vital pathological process of rheumatoid arthritis and osteoarthritis, remains to be elucidated. The effects and the mechanism of icariin (ICA), which is a promising therapeutic agent in synovitis, was investigated in the present study. In addition, ferroptosis, a vital cell process involved in several diseases, was also studied in synovitis for the first time. Lipopolysacc haride (LPS)-induced synoviocytes served as a synovitis cell model. The cells were divided into control, LPS and experimental groups and were treated with different concentrations of ICA. Cell viability was determined by Cell Counting Kit-8 assay and cell death was determined by flow cytometry. The expression levels of proteins (GPX4, SLC7A11, SLC3A2L, TRF, Nrf2 and NCOA4) were measured by western blotting. Quantification of malondialdehyde (MDA), iron and glutathione peroxidase 4 (GPX4) activity levels were performed via using corresponding assay kits. Cell death was increased, and cell viability was decreased in LPS-induced synoviocytes. Furthermore, MDA levels and iron content were elevated and GPX levels was reduced in LPS-induced synoviocytes. Transferrin receptor protein 1 and nuclear receptor coactivator 4 were upregulated and proteins of the Xc-/GPX4 axis, as well as nuclear factor erythroid 2-related factor 2, were decreased by LPS treatment. All aforementioned LPS affects were alleviated by ICA via a concentration-dependent manner. ICA counteracted the effects of RSL3, a ferroptosis activator, on cell viability, lipid peroxidation, iron content and relative protein expression of ferroptosis in synoviocytes. ICA protects the cells from death in synoviocytes induced by LPS, via the inhibition of ferroptosis by activating the Xc-/GPX4 axis, which can be exploited as a new therapeutic strategy for synovitis.

Icariin inhibits hypoxia/reoxygenation‐induced ferroptosis of cardiomyocytes via regulation of the Nrf2/HO‐1 signaling pathway

“…These results suggested that ICA protects H/R‐induced cardiomyocytes by inhibiting ferroptosis. Consistently, ICA prevents lipopolysaccharide‐induced cell death in synoviocytes by suppressing ferroptosis [ 44 ].…”

Ferroptosis‐Inhibitory Effect and Possible Mechanisms of Ellagitannin Geraniin

“…Owing to that plant‐derived phenolics have been consumed by human beings for thousands of years and proven to play a safe and beneficial role, phenolics are thus postulated to be a library of safe ferroptosis inhibitors. In fact, some plant‐derived phenolic flavonoids have been indicated as natural ferroptosis‐inhibitors, such as galangin, [5] icariin, [6] and baicalein [7] . Recently, our team also found that quercetin and its Diels‐Alder anti ‐dimer could also act as ferroptosis‐inhibitors [8] .…”

Ferroptosis in Rheumatoid Arthritis: A Potential Therapeutic Strategy

“…Early studies have confirmed that glutathione peroxidase (GPX) activity in polymorphonuclear leucocytes of RA patients with high persistent disease activity is reduced (16). Luo et al (17) found that RSL3, a ferroptosis activator, can induce ferroptosis in synovial cells and aggravate synovitis. Transferrin receptor 1 (TFR1) and nuclear receptor coactivator 4 (NCOA4) were upregulated, but system Xc-(an amino acid transporter mediating the exchange of extracellular cystine and intracellular glutamate) and GSH-glutathione peroxidase 4 (GPX4), as well as nuclear factor erythroid 2-related factor 2 (Nrf2, a transcriptional factor that induces antioxidative and cytoprotective responses), were downregulated by RSL3 treatment.…”