Apigenin-Mediated ESCRT-III Activation and Mitophagy Alleviate LPS-Induced Necroptosis in Renal Cells

Apigenin (API) is a flavonoid widely distributed in vegetables and fruits that exhibits numerous biological functions. Lipopolysaccharide (LPS), a key component of the outer membrane of Gram-negative bacteria, can cause kidney injury when released into the bloodstream. Necroptosis is a form of programmed cell death characterized by the rupture of cell membranes. Excessive occurrence of necroptosis can lead to substantial damage to cells and tissues. In the study, we discovered that API could mitigate LPS-induced kidney injury in mice and alleviate LPS-induced necroptosis in Normal Rat Kidney-52E (NRK-52E) cells by targeting the mitochondrial reactive oxygen species (mtROS)-RIPK3-MLKL pathway. Further mechanistic studies revealed that API could potentially activate the endosomal sorting complexes required for transport-III (ESCRT-III), and activated ESCRT-III could repair cell membrane rupture caused by LPS-induced necroptosis. Simultaneously, we discovered that activated ESCRT-III could promote mitophagy, which facilitates the timely removal of damaged mitochondria and reduces intracellular mtROS levels. In conclusion, our results suggested that API alleviates LPS-induced renal cell necroptosis by activating ESCRT-III-dependent membrane repair and mitophagy. Our study provides new insights into the daily dietary intake of API to alleviate kidney injury caused by LPS.