Introduction: Hepatocellular carcinoma (HCC) remains a highly aggressive malignancy with limited therapeutic options, and the development of resistance to sorafenib-the first-line systemic treatment for advanced disease-significantly compromises clinical outcomes. Understanding the mechanisms underlying the acquisition of sorafenib resistance is crucial, as it not only limits the drug's therapeutic efficacy but also promotes tumor progression and treatment failure in patients with advanced HCC. Previously, we demonstrated that MCPIP1 can partially reverse sorafenib resistance in clear cell renal cell carcinoma. Therefore, the main aim of our research is to investigate the molecular basis of sorafenib resistance in HCC and the potential protective role of MCPIP1 during this process. Material and Methods: We used two HCC cell lines-HUH7 and SNU449-continuously treated with sorafenib. We analyzed cell proliferation, migration, and invasion. Next, we performed mass spectrometry analysis and validated the obtained results using western blotting and real-time PCR. To determine changes in cell phenotype, we conducted a series of immunohistochemical stainings. To examine the effect of MCPIP1, wild-type and sorafenib-resistant cell lines were transduced to overexpress MCPIP1 along with appropriate controls. Results and Discussion: Exposure to sorafenib induces notable phenotypic changes in HCC cell lines. In HUH7 cells, which normally display an epithelial phenotype, prolonged treatment is commonly associated with a shift toward a more mesenchymal-like state, characterized by reduced cell-cell adhesion and pronounced morphological alterations, including the formation of membrane protrusions such as filopodia and lamellipodia. SNU449 cells, which already exhibit relatively mesenchymal features, further reinforce this phenotype under sorafenib pressure, displaying increased motility and a more invasive appearance. Consistent with these observations, we detected substantial reorganization of the actin cytoskeleton as well as elevated levels of structural and regulatory proteins such as vimentin, RhoA, RhoB, and Ras. Together, these changes reflect a transition toward epithelial-to-mesenchymal characteristics. Interestingly, all resistant cells exhibited a significantly decreased level of MCPIP1. Following MCPIP1 overexpression, we observed a reduction in EMT-related markers, including vimentin and Snail, suggesting a potential suppressive role of MCPIP1 in the development of sorafenib resistance. Conclusions: In conclusion, our results indicate that sorafenib resistance in HCC is associated with EMT and cytoskeletal remodeling, and that MCPIP1 may act as a suppressor of this process, representing a potential therapeutic target to overcome resistance. This study was supported by National Science Center grant no. 2022/47/B/NZ5/02724.