Quercetin attenuated necroptosis and apoptosis caused by LPS-induced mitochondrial function dysfunction through the METTL3-mediated PTEN mA methylation/PI3K/AKT signaling in broiler livers.

Background: Quercetin (QUE), a natural flavonoid, offered an efficient protection against organism injury. N6-methyladenosine (mA) methylation is considered to be the most prevalent and abundant modifications involved in various diseases.

Purpose: We sought to explore protective roles of QUE in mitigating necroptosis and apoptosis triggered by LPS-induced imbalances in mitochondria dynamic and energy metabolism in broiler livers, with a focus on mA methylation modulation.

Study Design/methods: We used LPS as a stimulus and treated with QUE to establish this in vivo and in vitro. In addition, we treated LMH cells with siMETTL3 (80 nM) to determine its detailed mechanism.

Results: Our findings revealed QUE significantly decreased METTL3 expression, leading to a decrease in PTEN mA methylation and factors related to mitochondria fission, necroptosis, and apoptosis in the QUE+LPS group. In contrast, QUE treatment promoted the expression levels of marker factors for mitochondria fusion, energy metabolism, anti-apoptosis, and PI3K/AKT compared with the LPS group. Additionally, an increase of ΔΨm, ATP content, and ATPase activity was observed. AO/EB staining, Flow cytometry and TUNEL assays confirmed QUE inhibited LPS-induced apoptosis and necroptosis. Molecular docking analysis and cellular thermal shift assay supported an interaction between QUE and METTL3.

Conclusion: In summary, QUE mitigated necroptosis and apoptosis triggered by LPS-induced disorders of mitochondrial kinetic and metabolic processes in broiler livers through its interaction with METTL3, regulating PTEN mA methylation/PI3K/AKT signaling pathway. This study enhances our understanding of biological functions for QUE and lays a theoretical foundation for developing new therapeutic interventions, highlighting its potential value.