Herein, we revealed that C3 was upregulated in PTX-resistant NSCLC cells, and its active fragment C3b translocated into the nucleus to regulate gene transcription indirectly by interacting with the SIN3A/HDAC corepressor complex; thus, the subsequent downregulation of GADD45D induced PTX resistance. Here, C3 is linked to non-small cell lung carcinoma.