Irisin alleviates ferroptosis in LPS-induced acute kidney injury via regulating FGL2

Sepsis-associated acute kidney injury (SA-AKI) is significantly associated with high morbidity and mortality rates. Emerging evidence has suggested that ferroptosis plays a key role in AKI. It has been also reported that irisin exerts anti-inflammatory, anti-oxidative and anti-apoptotic properties. However, its protective effect, particularly via regulating ferroptosis, in AKI remains unclear. Therefore, the present study aimed to investigate the potential of irisin to restrain ferroptosis and relieve SA-AKI via activating fibrinogen-like 2 (FGL2). For the in vivo experiments, a lipopolysaccharide (LPS)-induced AKI model was established in wildtype and FGL2^-/- mice. The effects of irisin in vitro were assessed in LPS-induced HK-2 cells. The results demonstrated that irisin could alleviate AKI, and attenuate ferroptosis and mitochondrial dysfunction in LPS-induced mice. However, these effects were partly abolished in FGL2^-/- mice. Additionally, the results revealed that irisin inhibited reactive oxygen species accumulation and malondialdehyde levels, while increasing superoxide dismutase activity and glutathione levels in HK2 cells. However, the protective effects of irisin on LPS-induced HK-2 cells were abrogated following FGL2 silencing. In conclusion, irisin could protect against SA-AKI via conferring resistance to ferroptosis through activating FGL2. These findings indicated that irisin could represent a potential therapeutic approach for the treatment of SA-AKI.