Tryptophan Suppresses FTH1‐Driven Ferritinophagy, a Key Correlate of Prognosis in Hepatocellular Carcinoma

ABSTRACT Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options. Ferritinophagy, an autophagy‐dependent process regulating iron metabolism, has emerged as a key contributor to ferroptosis and tumour progression. This study hypothesised that the ferritinophagy‐related gene FTH1 drives HCC pathogenesis by modulating tryptophan metabolism and reactive oxygen species (ROS)‐dependent ferroptosis. To test this, we first analysed TCGA data to identify prognostic ferritinophagy genes, revealing FTH1 as a critical risk factor. Functional experiments using FTH1 ‐knockdown/−overexpressing HCC cell lines and xenograft models demonstrated that FTH1 enhances proliferation, migration, and tumour growth by upregulating CYP1A1/CYP1A2 in the tryptophan pathway, thereby increasing the synthesis of 6‐hydroxymelatonin (6‐HMT). Mechanistically, 6‐HMT suppressed ROS and ferroptosis by inhibiting cytochrome P450 oxidoreductase (POR). Concurrently, intracellular tryptophan levels were found to inhibit NCOA4‐mediated selective autophagy of FTH1, stabilising FTH1 levels and promoting tumour survival. Collectively, our findings establish FTH1 as a central regulator of ferritinophagy in HCC and reveal its dual role in linking tryptophan metabolism to redox homeostasis. This result provides a hint of how FTH1 influences HCC pathogenesis and positions the tryptophan metabolism pathway as a promising therapeutic target.