FBXO6 ubiquitinates MAOA to promote monoamine neurotransmitter accumulation and tumor growth in HCC

Monoamine neurotransmitters dopamine and 5-hydroxytryptamine (serotonin, 5-HT), traditionally implicated in the central nervous system, are increasingly recognized as contributors to hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms remain unclear. Here, we demonstrate that the E3 ubiquitin ligase F-box-only protein 6 (FBXO6) is highly expressed in HCC patients. FBXO6 promotes accumulation of 5-HT and dopamine in HCC by mediating K48-linked ubiquitination and degradation of monoamine oxidase A (MAOA). Elevated monoamine levels activate their cognate receptors, triggering the PI3K/AKT/mTOR signaling axis. Simultaneously, these neurotransmitters induce transglutaminase 2 (TGM2)-dependent histone monoaminylation (H3Q5ser and H3Q5dop), forming a synergistic oncogenic circuit that drives HCC development. Clinical specimens reveal a strong inverse correlation between FBXO6 and MAOA protein levels, validating this regulatory axis. Preclinical studies demonstrate that combined treatment with the mTOR inhibitor everolimus and the TGM2 inhibitor GK921 exerts synergistic antitumor effects against FBXO6-driven HCC, providing a rational therapeutic strategy for patients with FBXO6 overexpression.