GOT1 inhibits hepatocellular carcinoma progression by regulating SLC25A5-dependent mitochondrial apoptosis.

Hepatocellular carcinoma (HCC), the most common subtype of primary liver cancer, is characterized by a poor prognosis, with most patients diagnosed at advanced stages that are unresectable and resistant to targeted therapies. This underscores the critical need for novel therapeutic targets. In this study, we investigated the role of glutamate-oxaloacetate transaminase 1 (GOT1) in HCC progression and evaluated its therapeutic potential. GOT1 expression was markedly downregulated in HCC tissues compared with adjacent non-tumor tissues, and higher GOT1 expression correlated with improved patient survival. Functional experiments revealed that overexpression of GOT1 suppressed HCC cell proliferation and tumor growth while promoting apoptosis both in vitro and in vivo. Mechanistically, integrated transcriptome sequencing and mass spectrometry identified solute carrier family 25 member 5 (SLC25A5) as a GOT1-interacting partner. GOT1-induced oxidative stress, mitochondrial membrane depolarization, and activation of the apoptotic cascade were mediated through upregulation of SLC25A5; Conversely, SLC25A5 knockdown rescued these phenotypic effects. Importantly, adeno-associated virus-mediated delivery of GOT1 (AAV-TBG-GOT1) significantly inhibited tumor growth in preclinical HCC models, underscoring its translational relevance. Collectively, these results establish GOT1 as a tumor suppressor in HCC that acts via SLC25A5-dependent mitochondrial apoptosis and propose GOT1 as a promising prognostic indicator and therapeutic target for HCC.