HLF, also known as hepatic leukemia factor, is a master transcription factor with significant biological importance. It is involved in various biological processes, including regulating cell fate, and is associated with multiple signaling pathways such as Hippo, WNT/β -catenin, and JAK2/STAT3 [1,3,4]. HLF has been implicated in the development and progression of several malignancies and plays a role in hematopoietic stem cell state definition [1,2].

In triple-negative breast cancer (TNBC), HLF acts as an oncoprotein. It is regulated by TGF-β1 secreted by tumor-associated macrophages (TAMs), then transactivates GGT1 to promote ferroptosis resistance, cell proliferation, metastasis, and cisplatin resistance. TNBC cells, in turn, secrete IL-6 to activate the JAK2/STAT3 axis in TAMs, inducing TGF-β1 secretion, forming a feed-forward circuit [1].

In ovarian cancer, HLF upregulation promotes cancer progression and chemoresistance by transcriptionally activating YAP1 and modulating the Hippo signaling pathway [3].

In intrahepatic cholangiocarcinoma, HLF is upregulated via METTL3-dependent m6A methylation, promoting tumorigenicity through the FZD4/β-catenin signaling pathway [4].

In hepatocellular carcinoma, HLF is reactivated by SOX2 and OCT4, transactivates c-Jun to drive tumor initiation and progression, and is associated with sorafenib resistance [5].

In conclusion, HLF plays crucial roles in the development and progression of multiple cancers, including TNBC, ovarian cancer, intrahepatic cholangiocarcinoma, and hepatocellular carcinoma. Studies on HLF provide potential therapeutic targets for these malignancies. Additionally, HLF is important in defining the human hematopoietic stem cell state [1,2,3,4,5].