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KMO downregulation promotes hepatocellular carcinoma growth via 3‑HAA‑mediated mitochondrial mass and function imbalances
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Kynurenine (Kyn) 3‑monooxygenase (KMO) is a key enzyme of the tryptophan (Try)‑Kyn pathway and is located on the outer membrane of mitochondria. Notably, it has not yet been elucidated as to whether KMO is involved in hepatocellular carcinoma (HCC) progression by affecting mitochondria. In the present study, KMO was revealed to be downregulated in HCC patients and this downregulation was associated with a poor prognosis. Notably, the downregulation of KMO promoted the proliferation and migration of HCC cells and increased mitochondrial mass. The levels of the Try metabolite 3‑hydroxyanthranilic acid (3‑HAA) were elevated in HCC cells overexpressing KMO. The results indicated that 3‑HAA may inhibit HCC cell growth promoted by KMO downregulation and reverse the KMO downregulation‑induced increase in mitochondrial mass. Furthermore, KMO and 3‑HAA were shown to regulate the expression of the transcription factor nuclear receptor subfamily 4 group A member 1 (NR4A1) and reduce NR4A1 mitochondrial translocation, thus inhibiting the growth of HCC cells. In summary, the current study elucidated that low KMO expression in HCC affects mitochondrial mass and function by reducing the level of the Try metabolite 3‑HAA, downregulating the expression of NR4A1 and promoting its mitochondrial translocation, which in turn may promote the progression of HCC. These findings provide new insights into the treatment of HCC, potentially targeting the mitochondria and the Try‑Kyn pathway.
.Pubmed ID: 41543194
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