Semaphorin 5A suppresses ferroptosis through activation of PI3K-AKT-mTOR signaling in rheumatoid arthritis

Abstract

Abnormal activation of synovial fibroblasts (SFs) plays an important role in rheumatoid arthritis (RA), the mechanism of which remains unknown. The purpose of our study is to comprehensively and systematically explore the mechanism for Semaphorin 5A-mediated abnormal SF activation in RA. Here, we found that Semaphorin 5A levels were significantly higher in synovial fluid and synovial tissue from RA patients compared with osteoarthritis patients. We further found that the mRNA level and protein abundance of Plexin-A1 was elevated in RA SFs compared with OA SFs, while Plexin-B3 expression showed no significant difference. The increased Semaphorin 5A in RA synovial fluid was mainly derived from CD68+ synovial macrophages, and the elevation led to increased binding between Semaphorin 5A and its receptors, thereby promoting cytokine secretion, proliferation, and migration, and decreasing apoptosis. Moreover, the effect of Semaphorin 5A on enhancing activation (cytokine secretion, cell proliferation and migration) and reducing apoptosis of SFs was significantly abolished after knockdown of Plexin-A1 and Plexin-B3 by small interfering RNA. Transcriptome sequencing and protein array detection revealed that Semaphorin 5A activated the PI3K/AKT/mTOR signaling pathway and inhibited ferroptosis. Morphologically, transmission electron microscopy results showed that Semaphorin 5A could significantly eliminate the mitochondrial diminution, membrane density increased and crest ruptured of SFs induced by ferroptosis inducer RSL3. Mechanistically, Semaphorin 5A enhanced GPX4 expression and SREBP1/SCD-1 signaling by activating the PI3K/AKT/mTOR signaling pathway, thus suppressing ferroptosis of RA SFs. In conclusion, our study provided the first evidence that elevated Semaphorin 5A in RA synovial fluid promotes SF activation by suppressing ferroptosis through the PI3K/AKT/mTOR signaling pathway.

Olaparib synergizes with arsenic trioxide by promoting apoptosis and ferroptosis in platinum-resistant ovarian cancer

“…The Annexin V + / PI– fraction represents apoptotic cells while Annexin V + / PI + may include both late apoptotic and necrotic cells. Our data, together with previous studies [ 39 , 56 , 58 – 61 ], demonstrated a subset of cells with Annexin V-/ PI + in ferroptosis, detected by Annexin V/PI assay, and our subsequent results further verified the co-treatment-induced ferroptosis. However, some studies indicated that cells with Annexin V + / PI + represented the initiation process of ferroptosis, which needs to perform time-course experiments to elucidate.…”

Increased ATF2 expression predicts poor prognosis and inhibits sorafenib-induced ferroptosis in gastric cancer

“…MDA is a final product of lipid peroxidation, which shows a positive correlation with ferroptosis [ 21 ]. The MDA concentration in GC cells was measured by the thiobarbituric acid method using a cell MDA assay kit (A003-4, Jiancheng Bioengineering Institute, Nanjing, China).…”

Platelet-rich plasma ameliorates lipopolysaccharide-induced cardiac injury by inflammation and ferroptosis regulation

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