Methylation Regulation of LPCAT3 Improves Osteoarthritis by Regulating ACSL4 to Inhibit Chondrocyte Ferroptosis

Abstract

With the increasing aging population in China, the incidence rate of knee osteoarthritis is expected to rise annually. Therefore, we conducted a study to investigate the crucial role of LPCAT3 in osteoarthritis and its underlying mechanisms. We collected samples from normal volunteers (<i>n</i> = 12) and patients with osteoarthritis (<i>n</i> = 12) at our hospital. It was observed that LPCAT3 mRNA expression was reduced and positively correlated with IL-1β mRNA expression in patients with osteoarthritis. In a mouse model, LPCAT3 mRNA and protein expression were found to be suppressed. Furthermore, in an <i>in vitro</i> model, the enrichment level of LPCAT3 mRNA was inhibited by a specific m6A antibody through si-METTL3. Si-METTL3 also reduced the stability of LPCAT3 mRNA in the <i>in vitro</i> model. The inhibition of LPCAT3 was found to exacerbate osteoarthritis in the mouse model. Additionally, LPCAT3 was shown to reduce inflammation in the<i> in vitro</i> model. It was also observed that LPCAT3 reduced chondrocyte ferroptosis by inhibiting mitochondrial damage. LPCAT3 protein was found to interact with ACSL4 protein, and its up-regulation suppressed ACSL4 expression in the <i>in vitro</i> model. ACSL4 was identified as a target of LPCAT3 for suppressing mitochondrial damage in the <i>in vitro </i>model. In conclusion, this study demonstrates that LPCAT3 improves osteoarthritis by regulating ACSL4 to inhibit chondrocyte ferroptosis, thus providing a novel target for the treatment of osteoarthritis.

Correlation between RNA N6-methyladenosine and ferroptosis in cancer: current status and prospects

“…In vitro models, ACSL4 was identified as a target for LPCAT3 to inhibit mitochondrial damage. Methylation regulation of LPCAT3 improves osteoarthritis by regulating ACSL4 to inhibit chondrocyte ferroptosis ( Habaxi et al, 2024 ).…”