STBD1 mediates the crosstalk between glycogen and lipid droplets in clear cell renal cell carcinoma

The accumulation of lipid droplets (LDs) and glycogen is a major hallmark of clear cell renal cell carcinoma (ccRCC), yet their interplay remains unclear. By proteomic profiling of 50 ccRCC tumors, we observe activation of glycogen- and LD-related pathways. Using proximity labeling of the LD proteome, we identify starch-binding domain-containing protein 1 (STBD1), a glycogen-binding protein involved in glycophagy, as a novel LD component. Further mechanistic investigation shows that STBD1 targets LDs via N-terminal myristoylation and mediates glycogen-LD colocalization. Its depletion decreases LD abundance and impairs both glycophagy and lipophagy, suggesting a critical role of STBD1 in both the biogenesis and autophagic degradation of LDs. Furthermore, STBD1 knockdown alters lipid composition, enhances ferroptosis sensitivity, and suppresses tumor growth both in vitro and in vivo. Collectively, our findings establish STBD1 as a critical mediator of glycogen-LD crosstalk and highlight its potential as a therapeutic target in ccRCC.