SH3GLB1 mediates tumor cell resistance to tyrosine kinase inhibitors by regulating mitophagy

Abstract Tyrosine kinase inhibitors (TKIs) have been widely utilized in cancer treatment, but their effectiveness was often hampered by the development of drug resistance. A better understanding of the TKIs resistance mechanism is beneficial to improving therapeutic strategies. Our study found that SH3GLB1 expression was elevated in drug-resistant cells by transcriptome sequencing and correlated with poor prognosis. Silencing SH3GLB1 substantially abrogated TKIs resistance in tumor cells. Single-cell RNA sequencing analysis demonstrated a strong correlation between SH3GLB1 and mitophagy. Subsequent experiments confirmed that elevated SH3GLB1 expression promoted TKIs-induced intracellular mitophagy, accompanied by decreased intracellular reactive oxygen species (ROS) levels, thereby attenuating TKIs-induced cytotoxicity. Mechanistically, we elucidated that SH3GLB1 interacted with the ATG5-ATG12-ATG16L1 complex to modulate mitophagic activity. Additionally, CDK1 expression was associated with changes in SH3GLB1 protein abundance and ubiquitination, suggesting a potential role for CDK1 in regulating SH3GLB1 stability. Collectively, our findings identify SH3GLB1 as a regulator of mitophagy-associated TKIs resistance in HCC cells. SH3GLB1 interacts with the ATG5-ATG12-ATG16L1 complex to promote mitochondrial clearance and reduce ROS accumulation, whereas CDK1 expression was associated with changes in SH3GLB1 ubiquitination and protein abundance, suggesting that CDK1 may participate in the regulation of SH3GLB1 protein stability. These findings suggest that targeting SH3GLB1 may represent a potential strategy for restoring TKIs sensitivity.