ATF3-SLC7A7 Axis Regulates mTORC1 Signaling to Suppress Lipogenesis and Tumorigenesis in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) poses a substantial global health burden, with poor prognosis and high mortality rates. Dysregulated lipid metabolism has emerged as a critical driver of HCC progression. While mTORC1 signaling is known to promote lipid synthesis in HCC, the regulatory mechanisms governing mTORC1 remain largely unclear. Here, we demonstrate that mTORC1 inhibition significantly reduces lipogenesis in HCC and uncover a regulatory axis involving the transcription factor ATF3 and the leucine-arginine transporter SLC7A7. Transcriptomic analysis of HCC patients reveals an inverse correlation between ATF3 expression and lipid synthesis, a finding corroborated by experimental validation. Mechanistically, ATF3 suppresses mTORC1 signaling, thereby inhibiting lipid biosynthesis, with SLC7A7 identified as a key intermediary in this process. Specifically, ATF3 binds to the enhancer region of SLC7A7, driving its transcriptional activation and subsequently restraining mTORC1 activity. Functional assays in ATF3-overexpressing and -knockdown HCC cell lines further confirm ATF3's role as a tumor suppressor. Our study identifies a novel ATF3-SLC7A7-mTORC1 regulatory axis that attenuates lipogenesis and tumorigenesis in HCC, establishing a critical link between lipid metabolism and hepatocarcinogenesis. These findings offer new insights into potential therapeutic targets for the treatment of HCC.