USP18 promotes ferroptosis in lipopolysaccharide-induced human kidney organoids by stabilizing STING1.

Abstract

Sepsis-induced acute kidney injury (SI-AKI) is a severe condition with limited therapeutic options, resulting in poor prognosis. Ferroptosis exacerbates the damage caused by SI-AKI, but the mechanisms regulating ferroptosis, especially those involving ubiquitination regulators, remain poorly understood. Here, we used a lipopolysaccharide (LPS)-induced human kidney organoid (HKO) model to investigate ferroptosis in SI-AKI. RNA sequencing (RNA-seq) analysis of control and LPS-treated HKOs revealed USP18 as the only upregulated ubiquitin-specific protease (USP) in response to LPS. Further investigations showed that depletion of USP18 significantly reduced ferroptosis in LPS-induced HKOs. To explore the mechanism underlying USP18's pro-ferroptotic role, we screened four ferroptosis-related drivers and identified STING1 as the key interacting protein with USP18. Mechanistically, USP18 directly binds to STING1, deubiquitinates it, and prevents its proteasomal degradation in HKOs. Overexpression of STING1 in USP18-deficient HKOs exacerbated ferroptosis, indicating that STING1 is crucial for mediating USP18's ferroptosis-promoting function in LPS-induced HKOs. Together, these findings establish that USP18-STING1 axis plays role in LPS-induced ferroptosis in HKOs, illuminating that targeting USP18-STING1 could provide neoteric therapeutic approach for treating SI-AKI.