Zinc Finger Protein 143 Bidirectionally Regulates the Proliferation of Hepatocytes and Hepatocellular Carcinoma Cells via c‐Myc

ABSTRACT The transcription factor zinc finger protein 143 (ZNF143) plays a crucial role in regulating diverse biological processes, including cell cycle progression, development, and cellular differentiation. Similarly, c‐Myc is well‐established as a key regulator of cell proliferation, differentiation, and metabolic homeostasis. While studies have demonstrated ZNF143's involvement in the proliferation of both normal hepatocytes and hepatoma cells, the precise mechanisms underlying ZNF143‐mediated regulation of hepatocyte proliferation, as well as its potential functional interplay with c‐Myc in this process, remain to be fully elucidated. In this study, we investigated the dynamic expression patterns of ZNF143 and c‐Myc during distinct phases of liver regeneration using a 2/3 partial hepatectomy (PHx) mouse model. To elucidate the regulatory roles of these factors in hepatocyte proliferation, we employed the mouse normal hepatocyte line AML12 and the human hepatoma cell line Huh7 as experimental models. Through MTT, CCK‐8, EdU, quantitative real‐time PCR (qRT‐PCR), and Western blot, we examined the individual and combined effects of ZNF143 and c‐Myc on hepatocyte proliferation. Our findings reveal that ZNF143 inhibits proliferation and cell cycle progression in AML12 cells but promotes these processes in Huh7 cells. Notably, co‐overexpression (OE) of ZNF143 and c‐Myc in AML12 cells inhibited proliferation and cell cycle progression, suggesting that ZNF143 exerts a dominant regulatory effect over c‐Myc in normal hepatocytes. This study establishes a critical foundation for investigating the role of ZNF143 in hepatocyte proliferation in vivo, with potential implications for liver regeneration and transplantation therapies.