SART3 Activates CD36 Transcription by Recruiting FOXM1 and Activates PARP to Augment Cisplatin Resistance in Non-Small Cell Lung Cancer

Cisplatin resistance remains a major barrier to effective lung cancer treatment. In this study, we identified that SART3 is upregulated in cisplatin-resistant non-small cell lung cancer (NSCLC) cells and promotes DNA damage repair. SART3 deletion sensitized cells to cisplatin, whereas re-expression restored resistance. Mechanistically, SART3 enhanced DNA repair mainly through the PARP pathway rather than ATM or DNA-PK, and its deletion increased gH2AX levels and reduced BrdU incorporation. Metabolic analysis revealed that SART3-driven resistance relied on elevated fatty acid (FA) β-oxidation rather than glycolysis. SART3 promoted FA uptake by upregulating CD36, resulting in increased oxidative phosphorylation, ATP production, and enhanced DNA repair. Targeting FA metabolism with CPT1A inhibitors or CD36 antagonists, or blocking PARP activity, significantly reversed SART3-mediated resistance. Further, SART3 recruited FOXM1 to activate CD36 transcription by modulating H2b deubiquitination. In vivo, inhibition of the SART3-CD36-PARP axis effectively suppressed tumor growth and restored cisplatin sensitivity. Collectively, our findings reveal that SART3-driven metabolic reprogramming and DNA repair underpin cisplatin resistance, providing potential therapeutic strategies to overcome drug resistance in NSCLC.