Targeting iRhom2-mediated PANoptosis ameliorates acute kidney injury

Although PANoptosis plays a pivotal role in the pathogenesis of acute kidney injury (AKI), the underlying regulatory mechanisms and effective therapeutic strategies remain largely unexplored. In this study, we report a novel function of inactive rhomboid 2 (iRhom2), encoded by the Rhbdf2 gene, in promoting PANoptosis in tubular epithelial cells (TECs). First, iRhom2 expression was induced in the kidneys of mice with ischemia/reperfusion injury (IRI) or cisplatin-induced AKI, which was further confirmed in the kidneys of patients with biopsy-proven acute tubular necrosis (ATN). Moreover, iRhom2 levels positively correlated with serum creatinine (SCr) and blood urea nitrogen (BUN) levels in ATN patients. Functionally, the tubule-specific deletion of Rhbdf2 alleviated AKI progression. Mechanistically, iRhom2 facilitated the trafficking of ATF6 from the endoplasmic reticulum (ER) to the Golgi apparatus, leading to its proteolytic cleavage. Then, cleaved ATF6 (cATF6) subsequently translocated to the nucleus and upregulated the expression of HSP90, which acts as a positive regulator of IFN regulatory factor 1 (IRF-1), thereby promoting the formation of the RIPK1 PANoptosome in TECs. Importantly, both the silencing of Rhbdf2 using neutrophil membrane-enveloped nanoparticles and the pharmacological inhibition of iRhom2 with sulforaphane alleviated renal damage in AKI model mice. Collectively, these results reveal iRhom2 as a key regulator of PANoptosis and suggest that targeting iRhom2 may represent a potential therapeutic strategy for AKI.