TRIM21-mediated ubiquitination of PARP1 regulated by the PI3K/AKT-STAT5A axis suppresses small cell lung cancer.

Abnormal accumulation of Poly(ADP-ribose) polymerase 1 (PARP1) promotes cancer progression, yet its stabilization mechanisms remain unclear. Here, we identify E3 ubiquitin ligase tripartite motif-containing 21 (TRIM21) as a PARP1-binding partner. PARP1 interacts directly with TRIM21 via its 662-908 domain, while the PRY-SPRY domain of TRIM21 is essential for this binding. TRIM21 facilitates PARP1 polyubiquitination at residue K654, leading to its degradation. In small cell lung cancer (SCLC), TRIM21 is significantly downregulated, and its tumor-suppressive function is partly mediated through the degradation of PARP1, supporting genomic stability. Additionally, the PI3K/AKT pathway transcriptionally suppresses TRIM21 via transcription factor STAT5A, thereby stabilizing PARP1. Importantly, combining the PI3K/AKT inhibitor PKI-587 with the PARP inhibitor BMN673 synergistically inhibits tumor growth across multiple SCLC models, including cell lines, patient-derived organoids, and xenograft models. Collectively, our findings define a "PI3K/AKT-STAT5A-TRIM21-PARP1" axis critical for SCLC progression and propose its dual inhibition as a promising therapeutic strategy.