Tsai, Li-TingLi-TingTsaiWu, Cheng-TienCheng-TienWuLiu, Chieh-YunChieh-YunLiuCHIH-KANG CHIANGSHING-HWA LIU2026-01-072026-01-072025-07-12https://scholars.lib.ntu.edu.tw/handle/123456789/735128Chronic kidney disease (CKD) has become a major global public health concern, with both its incidence and prevalence continuing to rise. Zinc protoporphyrin (ZnPP) is formed during heme biosynthesis when zinc is incorporated into the protoporphyrin IX ring in place of iron, a process that is markedly enhanced under conditions of iron deficiency or impaired iron metabolism. Elevated ZnPP levels observed in patients with renal failure result from a variety of pathogenic mechanisms. Heme oxygenase (HO)-1, a key enzyme in heme catabolism, degrades heme into biliverdin (subsequently converted to bilirubin), carbon monoxide, and ferrous iron. However, the relationship between ZnPP and HO-1 in the kidney, as well as their roles in CKD progression, still remains to be clarified. In the present study, an adenine-induced CKD mouse model was utilized to investigate the regulatory role of ZnPP in HO-1 expression and activity and its involvement in CKD progression in vivo. CKD mice exhibited substantial ZnPP accumulation, accompanied by significant upregulation of renal HO-1 protein expression and enzymatic activity, along with pronounced renal dysfunction. To further elucidate the role of ZnPP, N,N,N',N'-tetrakis (2-pyridinylmethyl)-1,2-ethanediamine (TPEN), a potent zinc chelator as a ZnPP formation inhibitor, was administered. TPEN treatment markedly attenuated ZnPP accumulation, decreased HO-1 protein expression and enzymatic activity, and ameliorated renal pathological changes in CKD mice. Collectively, these findings suggest that endogenous ZnPP may act as an activator of HO-1 in the kidney and contribute to the pathogenesis of CKD. Targeting ZnPP-mediated HO-1 pathway may offer a novel therapeutic strategy for CKD management.enChronic kidney diseaseHeme oxygenase-1KidneyZinc protoporphyrin[SDGs]SDG3journal article10.1016/j.bbrc.2025.15201440381240