Genetic haploinsufficiency of POM121 exacerbates ischemia reperfusion injury induced acute kidney injury by promoting p53/p21-mediated cellular senescence.

Acute kidney injury (AKI) is a severe clinical syndrome with limited therapeutic options. Here, we identified a previously unrecognized role of the nuclear pore complex protein POM121 in AKI. Analysis of the public transcriptomic dataset GSE153625, together with qPCR, Western blot, and immunohistochemical validation, demonstrated that POM121 expression was markedly increased in ischemia-reperfusion injury (IRI)-induced AKI. Due to embryonic lethality of homozygous POM121 knockout mice, heterozygous POM121⁺/⁻ mice were used for functional studies. POM121 haploinsufficiency significantly aggravated renal dysfunction and tubular injury after IRI, accompanied by elevated serum creatinine (134.365 ± 28.363 vs. 227.917 ± 19.235μmol/L), blood urea nitrogen (24.027 ± 2.850 vs. 44.513 ± 3.541 mmol/L), and KIM-1 expression (approximately 1-2-fold increase). In contrast, POM121 overexpression alleviated renal injury. Consistently, POM121 knockout in TCMK1 cells exacerbated hypoxia/reoxygenation-induced injury. Mechanistically, POM121 was found to suppress p53/p21-mediated tubular epithelial cell senescence in AKI. Collectively, these results point to a protective function of POM121 in AKI via regulation of p53/p21-mediated cellular senescence.