USP1 promotes hepatocellular carcinoma progression by modulating mitophagy via stabilizing MCM3 to regulate the Keap1-Nrf2 axis.

Hepatocellular carcinoma (HCC) is a common malignant tumor with a high mortality rate. High mitophagy levels can promote hepatic tumor progression; therefore, inhibiting mitophagy may be a promising therapeutic strategy. This study shows that minichromosome maintenance protein 3 (MCM3) was upregulated in HCC. Knocking down suppressed the biological behaviors of tumor cells, promoted tumor cell apoptosis, and inhibited mitophagy. We found that USP1 binds to MCM3 and stabilizes it via deubiquitination of K48-linked ubiquitin chains. Excessive MCM3 proteins bind to Keap1, disrupting the Keap1-Nrf2 interaction and activating the Nrf2 signaling pathway to modulate mitophagy, promoting HCC progression. In addition, our experiments showed that MCM3 knockdown significantly suppressed xenograft tumor growth. In summary, MCM3 functions as a key oncoprotein. USP1-mediated deubiquitination of MCM3 influences the Keap1-Nrf2 axis, regulates mitophagy, and facilitates HCC progression. MCM3 may be a potential therapeutic target for liver cancer.