The hepatic dynamic triad is the upstream priority gate in hepatocellular carcinoma: a testable hypothesis

Hepatocellular carcinoma (HCC) arises when a mutation field is converted into a clone, and the hepatic dynamic triad sets the conversion rate. The triad has three axes: outflow (O; sinusoidal flow, bile flow, lymph, regeneration), storage–containment (S; blood volume, endothelial barrier, coagulation, iron and glycogen), and transport–distribution (T; bile acids, ammonia, porto-systemic shunt, albumin and glucose). G1 is the mutation field, G3 the energy and immune budget, and G2 the triad that converts mutations into clones. We searched PubMed/MEDLINE in 53 tracks, retrieved 5,194 candidates, and built a 3,002-record matrix with a 609-record core. Evidence is graded A to C; negative and conflicting results remain. G2 is the priority gate. G1-only models are inefficient: β-catenin S45 mice develop no spontaneous HCC at 12 months, and HBV transgenic mice are weak carcinogens alone. G2-initiated models develop spontaneous HCC: farnesoid X receptor deficiency, Mdr2/Abcb4 loss, and Abcb11 loss. G1+G2 combinations accelerate carcinogenesis, and G2+G3 combinations rewrite immune surveillance. The O axis yields a capillarization–retention chain. The S axis places the direct carcinogenic interface at S2+S4: congestive hepatopathy drives endothelial αV-YAP-CTGF signaling, fibrosis, portal hypertension, and liver carcinogenesis. S3 and S6 return no direct initiation readout; ammonia and shunt return none in this matrix. Bile-acid transport reaches HCC initiation and immunity. Arm groups are mainly single-target (622 single, 69 dual, 2 multi); no study combines all three gates. G2 is the upstream priority gate; O/S/T are measurable arm groups; a 2×2×2 factorial is the validation design.