HLF (hepatic leukemia factor) is a PAR bZIP transcription factor that functions as a sequence-specific DNA-binding transcription activator of RNA polymerase II, operating in the nucleus and chr17 1. HLF exhibits dual and context-dependent roles across biological processes. In cancer biology, HLF demonstrates opposing functions depending on tissue type. In triple-negative breast cancer, HLF acts as an oncoprotein, transactivating GGT1 to promote ferroptosis resistance and driving cell proliferation, metastasis, and chemoresistance through tumor-associated macrophage crosstalk 1. Similarly, HLF promotes gallbladder cancer stem cell expansion and gemcitabine resistance via TFEB-induced autophagy, while driving immune evasion 2. Conversely, in renal cell carcinoma, HLF suppresses lung metastasis by regulating LPXN expression and modulating actin cytoskeleton dynamics; BRG1-mediated epigenetic silencing of HLF promotes metastasis 3. Pan-cancer analyses show HLF expression is generally reduced in tumors, correlating with poor survival and drug resistance 4. In immune biology, HLF directs CD4+ tissue-resident memory T cell differentiation by upregulating tissue retention receptors while downregulating egress receptors, promoting proinflammatory responses through Bhlhe40 induction 5. In hematopoiesis, HLF is a hallmark transcription factor expressed in HSC-derived progenitors differentiated from pluripotent stem cells 6.