A Review of Liver Cancer Development Driven by the AP-1/c-Jun~Fra-2 Dimer through c-Myc

Hepatocellular carcinoma (HCC) ranks among the leading causes of cancer-related mortality worldwide. Recent epidemiological data demonstrate a rising incidence of HCC, which is further compounded by its insidious onset, poor prognosis, and limited therapeutic options. Elucidating its molecular pathogenesis and identifying viable therapeutic targets remain critical unmet needs. While prior studies have implicated members of the AP-1 (Activator Protein-1) transcription factor family (e.g., c-Fos and c-Jun) in hepatocarcinogenesis, the roles of Fos-related antigens (Fra-1 and Fra-2) remain poorly characterized. This study investigates the mechanistic interplay between c-Jun/Fra-2 heterodimers and the oncogenic driver c-Myca well-established molecular nexus in HCC pathogenesisunraveling their collective impact on HCC proliferation, inflammatory cascades, and tumorigenesis. Through a systematic literature review, this study delineates the pro-tumorigenic role of the c-Jun/Fra-2-Myc axis in murine HCC models. This paper elucidates how c-Jun-Fra-2 heterodimers transcriptionally regulate c-Myc to orchestrate core oncogenic programs. Integrative analysis of the HCC tumor microenvironment (TME) further reveals that c-Jun-Fra-2 overexpression induces TME remodeling, characterized by low-grade inflammation, mild fibrosis, and dyslipidemiakey permissive factors for HCC progression. The findings underscore the pivotal role of c-Jun-Fra-2 heterodimers in HCC pathogenesis, wherein their upregulation of c-Myc drives tumor initiation and progression. Notably, the c-Jun-Fra-2/c-Myc axis exhibits both reversibility and dependency, suggesting a therapeutic vulnerability. In HCC patients with elevated c-Jun-Fra-2 expression, pharmacological inhibition using the BET inhibitor JQ-1 significantly attenuates tumor growth, highlighting its potential as a precision therapy target. This work advances the molecular understanding of HCC and provides a rationale for targeted intervention in defined subsets.