Elucidating the molecular mechanisms underlying hepatocellular carcinoma (HCC) pathogenesis is crucial for the development of targeted therapies. Makorin-2 (MKRN2), a member of the makorin RING zinc finger protein family, acts as an E3 ubiquitin ligase that regulates post-translational modifications. Although emerging evidence implicates MKRN2 in the oncogenesis of various malignancies, its biological role in HCC remains poorly characterized. In this study, we found that MKRN2 expression was significantly upregulated in HCC and correlated with poor patient prognosis. To functionally validate the role of MKRN2, we performed CCK-8, colony formation, and EdU assays. Consistently, the results showed that MKRN2 depletion markedly attenuated the proliferative capacity of HCC cells. Subsequently, RNA-seq analysis in Huh-7 cells indicated that MKRN2 was involved in cell cycle regulation and the p38 MAPK signaling pathway. Furthermore, flow cytometry assays demonstrated that MKRN2 depletion arrested the cell cycle at the G1/S transition. Mechanistically, MKRN2 was shown to regulate c-Myc activation via the p38 MAPK pathway, thereby promoting cell cycle progression and enhancing proliferation. In addition, in vivo experiments confirmed that MKRN2 knockdown suppressed tumor growth in xenograft mouse models. In conclusion, our results demonstrate that MKRN2 promotes cell cycle progression and drives proliferation through activation of the p38 MAPK signaling pathway in HCC cells, highlighting its potential as a therapeutic target for HCC.
Wang et al. (2026) studied this question.