PRDM16 suppresses pyroptosis to attenuate the progression of AKI caused by rhabdomyolysis via upregulation of USP10.

Abstract

Previous studies have indicated that PRDM16 suppresses apoptosis and ferroptosis, thereby mitigating the development of AKI triggered by ischemia, cisplatin, and sepsis. Nevertheless, the exact function and control mechanisms of PRDM16 in rhabdomyolysis-induced AKI are not fully understood. In this investigation, PRDM16 was found to inhibit ferrous myoglobin-induced pyroptosis in Boston University mouse proximal tubule (BUMPT) cells. At the molecular level, PRDM16 binds to the USP10 promoter, enhancing its expression and subsequently inhibiting the NLRP3-Caspase1-GSDMD and Caspase3-GSDME pathways. Rhabdomyolysis-induced AKI was alleviated in PRDM16 KI mice, whereas PRDM16 KO exacerbated the condition. Furthermore, PNPs-encapsulated formononetin significantly attenuated the progression of rhabdomyolysis-induced AKI. In conclusion, PRDM16 suppresses pyroptosis and ameliorates rhabdomyolysis-induced AKI by regulating the USP10/NLRP3-Caspase1-GSDMD and Caspase3-GSDME pathways. PNPs-encapsulated formononetin emerges as a promising therapeutic strategy.