Loss of TFAM accelerates pentose phosphate pathway by unleashing G6PD oligomerization to drive hepatocarcinogenesis

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, characterized by complex pathogenesis and limited early diagnostic markers. Multi-omics analyses of mice and patients with primary liver tumors reveal significant depletion of oxidative phosphorylation (OXPHOS), despite increased tumor development. However, how this metabolic reprogramming supports tumor growth remains unclear. Here, we uncover the novel tumor-suppressive function of mitochondrial transcription factor A (TFAM), which is consistently downregulated in human HCC and correlates with poor prognosis. Hepatocyte-specific TFAM depletion promotes hepatocarcinogenesis by enhancing glucose-6-phosphate dehydrogenase (G6PD) activity, the rate-limiting enzyme of pentose phosphate pathway (PPP). Cytosolic TFAM directly binds G6PD and blocks its dimerization, restricting metabolism toward PPP, inhibiting nucleotide biosynthesis and slowing down tumor growth. Genetic or pharmacological inhibition of G6PD with 6-aminonicotinamide (6AN) reverses the tumorigenic effects of TFAM deficiency, highlighting a critical metabolic reprogramming in HCC progression. We further show silent mating type information regulation2 homolog-3 (SIRT3)-mediated deacetylation stabilizes TFAM, whereas SIRT3 downregulation promotes TFAM degradation via polyubiquitination. Together, our study reveals a novel mode of metabolic reprogramming due to the loss of TFAM and identifies the TFAM-G6PD axis as a metabolic vulnerability, offering a promising synthetic lethal therapeutic strategy for liver cancer.