Polygonum cuspidatum topped the herb–gene network and its signature stilbenes (resveratrol, polydatin) showed the strongest docking to NAFLD hub genes CDKN1A and CXCL2, while its classical function of “clearing damp-heat and invigorating blood” mirrors the disease’s inflammatory-metabolic block. This evidence concerns the gene CXCL2 and metabolic dysfunction-associated steatotic liver disease.