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Several studies have observed renal cell ferroptosis during cisplatin‐induced acute kidney injury (AKI). However, the mechanism is not completely clear. In this study, oxidized arachidonic acid (AA) metabolites are increased in cisplatin‐treated HK‐2 cells. Targeted metabolomics showed that the end product of pyrimidine biosynthesis is decreased and the initiating substrate of pyrimidine biosynthesis is increased in cisplatin‐treated mouse kidneys. Mitochondrial DHODH, a key enzyme for pyrimidine synthesis, and its downstream product CoQH2, are downregulated. DHODH overexpression attenuated but DHODH silence exacerbated cisplatin‐induced CoQH2 depletion and lipid peroxidation. Mechanistically, renal DHODH acetylation is elevated in cisplatin‐exposed mice. Mitochondrial SIRT3 is reduced in cisplatin‐treated mouse kidneys and HK‐2 cells. Both in vitro SIRT3 overexpression and in vivo NMN supplementation attenuated cisplatin‐induced mitochondrial DHODH acetylation and renal cell ferroptosis. By contrast, Sirt3 knockout aggravated cisplatin‐induced mitochondrial DHODH acetylation and renal cell ferroptosis, which can not be attenuated by NMN. Additional experiments showed that cisplatin caused mitochondrial dysfunction and SIRT3 SUMOylation. Pretreatment with mitochondria‐target antioxidant MitoQ alleviated cisplatin‐caused mitochondrial dysfunction, SIRT3 SUMOylation, and DHODH acetylation. MitoQ pretreatment protected against cisplatin‐caused AKI and renal cell ferroptosis. Taken together, these results suggest that mitochondrial dysfunction‐evoked DHODH acetylation partially contributes to renal cell ferroptosis during cisplatin‐induced AKI. [ABSTRACT FROM AUTHOR]

Sirtuin 3 (SIRT3) deacetylase is a key regulator for chemoresistance in acute myeloid leukemia (AML) cells due to its capability of modulating mitochondrial metabolism and reactive oxygen species (ROS). SIRT3 is de-SUMOylated by SUMO-specific peptidase 1 (SENP1), which enhances its deacetylase activity. Therefore, dysregulation of SIRT3 SUMOylation may lead to fortified chemoresistance in AML. Indeed, SIRT3 de-SUMOylation was induced by chemotherapeutic agents, which in turn, exacerbated resistance against chemotherapies in AML by activating SIRT3 via preventing its proteasome degradation. Furthermore, RNA-seq revealed that expression of a collection of genes was altered by SIRT3 de-SUMOylation including inhibition of transcription factor Hes Family BHLH Transcription Factor 1 (HES1), a downstream substrate of Notch1 signaling pathway, leading to increased fatty acids oxidation (FAO). Moreover, the SENP1 inhibitor momordin-Ic or HES1 overexpression synergized with cytarabine to eradicate AML cells in vitro and in xenograft mouse models. In summary, the current study revealed a novel role of SIRT3 SUMOylation in the regulation of chemoresistance in AML via HES1-dependent FAO and provided a rationale for SIRT3 SUMOylation and FAO targeted interventions to improve chemotherapies in AML. [ABSTRACT FROM AUTHOR]