Background: Ferroptosis is unique among different types of regulated cell death and closely related to organ injury. Whether ferroptosis occurs in sepsis-associated acute kidney injury (SA-AKI) is not clear. Nuclear factor-erythroid-2-related factor 2 (Nrf2) is crucial to the regulation of ferroptosis. We and others have shown that Maresin conjugates in tissue regeneration 1 (MCTR1) or other members of specialized pro-resolving mediators (SPMs) can actively regulate inflammation resolution and protect organs against injury in inflammatory diseases by activating the Nrf2 signaling. The aim of this study was to determine whether ferroptosis occurs in SA-AKI. Furthermore, we investigated the potential role and mechanism of MCTR1 in the regulation of ferroptosis in SA-AKI, which mainly focus on the Nrf2 signaling.Results: We demonstrated for the first time that ferroptosis is present in SA-AKI. Moreover, MCTR1 effectively suppressed ferroptosis in SA-AKI. Meanwhile, MCTR1 upregulated the expression of Nrf2 in the kidney of septic mice. Nrf2 inhibitor ML-385 reversed MCTR1-regulated ferroptosis and AKI, implying that Nrf2 is involved in the inhibitory effects of MCTR1 on ferroptosis in SA-AKI. Further, MCTR1 inhibited ferroptosis and elevated the expression of Nrf2 in LPS-induced HK-2 cells. However, Nrf2 siRNA offset the effect of MCTR1 on ferroptosis. Finally, we observed that MCTR1 ameliorates multi-organ injury and improves survival in animal models of sepsis.Conclusions: These data demonstrate that MCTR1 suppresses ferroptosis in SA-AKI through the Nrf2 signaling. Our study enriches the pathophysiological mechanism of SA-AKI and provides new therapeutic ideas and potential intervention targets for SA-AKI.

P38 MAPK (mitogen-activated protein kinase) is a critical regulator in lung inflammation. It can be inactivated by DUSP1 (dual-specificity phosphatase 1) which was identified as a putative target of miR-429. miR-429 mimics directly targeted to the 3′-UTR of the gene encoding DUSP1 may result in the translational attenuation of DUSP1. Moreover, the phosphorylation of p38 MAPK was prolonged after miR-429 mimic treatment. Additionally, miR-429 expression was sensitive to LPS (lipopolysaccharide) stimulation and the miR-429 mimics increased the production of pro-inflammatory cytokines. However, anti-miR-429 reduced the LPS-induced production of pro-inflammatory cytokines. These results provide direct evidence that miR-429 is involved in the LPS-induced inflammatory response. In parallel with miR-429, miR-200b and miR-200c, but not miR-200a or miR-141, shared similar effects. In vivo, LPS induced the expression of miR-429, miR-200b and miR-200c in lung. At the same time, inhibiting these miRNAs by anti-miRNAs attenuated the LPS-induced pulmonary inflammatory response and injury. These findings reveal that miR-429 possesses pro-inflammatory activities and may be a potential therapy target for LPS-induced lung injury.