Copper-mediated SEC14L3 promotes cuproptosis to inhibit hepatocellular carcinoma growth via ERK/YY1/FDX1 axis.

Cuproptosis, a copper-triggered cell death pathway, holds therapeutic potential for cancers, but its regulatory mechanisms in hepatocellular carcinoma (HCC) remain undefined. Despite SEC14L3's known roles in cellular signaling, its involvement in HCC progression and cuproptosis regulation is unclear. Here, we reveal that SEC14L3 expression is downregulated in HCC cells and tissues and correlates with advanced stages and poor prognosis. Copper-induced cuproptosis inhibits HCC cell viability, and SEC14L3 positively modulates cuproptosis in HCC cells by promoting DLAT lipoylation and its oligomerization. Mechanistically, SEC14L3-mediated cuproptosis suppressed HCC growth via the ERK/YY1/FDX1 axis both in vitro and in vivo. Additionally, copper enhanced the SEC14L3 expression, which in turn regulated ERK/YY1/FDX1 axis. Our findings show that copper-mediated SEC14L3 promotes cuproptosis via ERK/YY1/FDX1 axis, thereby inhibiting HCC growth. These insights provide a mechanistic foundation for targeting cuproptosis, advancing the development of SEC14L3-driven therapeutic strategies for HCC.