Liquid-liquid phase separation of GPS2-LATS1 promotes colorectal cancer progression by reprogramming lipid metabolism.

Aberrant lipid metabolism is a hallmark of colorectal cancer (CRC), yet the underlying regulatory mechanisms remain incompletely understood. Here, we identified G protein pathway suppressor 2 (GPS2) as a pivotal oncogenic driver that orchestrates lipid metabolic reprogramming to fuel CRC progression. Clinically, GPS2 is overexpressed in CRC and is correlated with aggressive phenotypes. Functionally, GPS2 depletion inhibits tumor growth in vitro and in vivo, whereas its overexpression accelerates malignancy. Mechanistically, GPS2 dual-regulates lipid metabolism by facilitating the nuclear translocation of sterol regulatory element-binding protein 1 (SREBP1) to activate lipid synthesis and by increasing peroxisome proliferator-activated receptor α (PPARα) transcription to promote fatty acid oxidation. Crucially, we revealed that GPS2 undergoes liquid-liquid phase separation (LLPS) in CRC cells, where it forms biomolecular condensates that promote oncogenic signaling. Through its coiled-coil domain, phase-separated GPS2 directly interacts with the C-terminal kinase domain of large tumor suppressor 1 (LATS1), a core kinase of the Hippo pathway, inducing LLPS of LATS1 and suppressing its activity. This inactivation releases YAP, which in turn amplifies SREBP1/PPARα-driven lipid metabolism. Rescue experiments confirmed that YAP reconstitution restores SREBP1 nuclear translocation and PPARα transcription upon GPS2 loss, establishing the LATS1-YAP axis as the central effector of GPS2-mediated lipid metabolic programming. Our study delineates a novel phase separation-dependent mechanism whereby GPS2 spatially reorganizes LATS1-YAP signaling to reprogram lipid metabolism and promote CRC progression, suggesting potential therapeutic targets for metabolic intervention in CRC.