<p>This study aims to elucidate the apoptotic effects of irisin in HepG2 cells. We examined the synergistic effects of irisin and gefitinib on the apoptosis of HepG2 cells. The MTT assay was utilized to evaluate the cytotoxic effects induced by irisin or gefitinib. Apoptosis induced by gefitinib, irisin, and their combined treatment was assessed using fluorescence microscopy and flow cytometry. The oxidative stress induced by reactive oxygen species and alterations in cell membrane potential were examined utilizing fluorescence microscopy and flow cytometry. The expression levels of genes associated with growth factors, oncogenes, apoptosis, and multidrug resistance were examined using RT-PCR. The best doses for HepG2 cells were established as 1.57 μM irisin and 15.66 μM gefitinib, administered for a length of 48 h. Flow cytometry analysis revealed a significant increase in apoptotic cells following treatment with irisin (16.91%), gefitinib (23.0%), and their combination (38.69%) in comparison to the control group. Furthermore, the proportion of cells impacted by ROS exhibited a notable rise: 8.17% in the irisin-treated cohort, 12.22% in the gefitinib-treated cohort, and 42% in the cohort receiving the combination of gefitinib and irisin. As a result of RT-PCR studies, it was observed that apoptosis was induced following the combination of irisin with gefitinib, and the expression levels of multidrug resistance genes, which were increased in response to gefitinib, were significantly suppressed. The findings of this study indicate that combining irisin with gefitinib could be an effective therapeutic approach against hepatocellular carcinoma.</p>