PDZK1‐ULK1 Axis Triggers Lipophagy to Inhibit Tumor Progression and Sunitinib Resistance in Clear Cell Renal Cell Carcinoma

ABSTRACT Clear cell renal cell carcinoma (ccRCC) is characterized by aberrant lipid droplet (LD) accumulation, which promotes tumor progression and sunitinib resistance. However, the underlying molecular mechanisms remain incompletely understood. This study shows that reduced PDZK1 expression correlates with LD accumulation and poor prognosis in ccRCC patients. Single‐cell RNA sequencing indicates that downregulated PDZK1 expression associates with impaired LD degradation in ccRCC cells. Functional studies demonstrate that PDZK1 inhibits LD accumulation by upregulating ULK1 expression and activating lipophagy, indicating the PDZK1‐ULK1 axis as a therapeutic target to enhance sunitinib efficacy. Mechanistically, CUT&Tag analysis reveals that LEF1 directly binds to the ULK1 promoter. PDZK1 interacts with LEF1 via its C‐terminus, sequestering LEF1 in the cytoplasm, thereby enhancing ULK1 transcription and autophagy activity. Pharmacological ULK1 activation with LYN‐1604 restores sunitinib sensitivity in PDZK1‐knockdown cells and synergizes with sunitinib in xenograft models, reducing tumor growth and LD accumulation. Clinical data demonstrate a strong correlation between ULK1 expression levels in tumor tissues and sunitinib response (AUC = 0.9063), suggesting its potential as a predictive biomarker. Collectively, the PDZK1‐ULK1 axis regulates LD homeostasis in ccRCC. Targeting this axis via ULK1 activation represents a novel strategy to overcome sunitinib resistance, with ULK1 as a potential biomarker for sunitinib efficacy.