Our findings support the following conclusions: (1) The adenoma originates from the autophagy-deficient hepatocytes; (2) Hepatocyte-derived HMGB1 stimulates tumor cell proliferation; (3) HMGB1 mediates the proliferative signal at least in part via RAGE in a paracrine mode; and (4) Tumors developed in the presence or absence of HMGB1 have significantly different transcriptomic profiles and mitochondria function could be an important mechanistic linker to tumor promotion. Here, HMGB1 is linked to neoplasm.