LRRC1 promotes hepatocellular carcinoma progression via FASN-dependent reprogramming of lipid metabolism

Hepatocellular carcinoma (HCC) remains a widespread malignancy with limited survival outcomes, creating a pressing demand for next-generation therapeutic approaches. Aberrant lipid metabolism is a hallmark of HCC progression, yet the underlying regulatory mechanisms remain elusive. We report that the LAP family protein leucine-rich repeat-containing 1 (LRRC1) acts as a key driver of hepatocellular carcinogenesis and de novo lipogenesis. Furthermore, clinical analyses highlight that LRRC1 is significantly enriched in HCC tissues and serves as a standalone prognostic biomarker for poor clinical outcomes. Functional analyses confirmed that LRRC1 drives malignant phenotypes, including proliferation and metastasis, in both cell cultures and xenograft models. Mechanistically, we reveal that E2F1-induced LRRC1 stabilizes fatty acid synthase (FASN) protein by inhibiting TRIM21-mediated ubiquitination. Consequently, LRRC1 orchestrates lipid metabolic reprogramming by promoting FASN-dependent de novo fatty acid synthesis and lipid droplet accumulation. In summary, this study uncovers the E2F1/LRRC1/FASN axis as a key driver of metabolic reprogramming in HCC, suggesting that targeting this pathway offers a promising therapeutic strategy.