FBXO44 Regulates Rac1 Spatiotemporal Dynamics: An Exploitable Therapeutic Vulnerability for Actin Cytoskeleton-Targeted Treatment in Gastric Cancer

The dynamic homeostasis of the cytoskeleton represents a critical vulnerability in tumor cells, yet the molecular mechanisms governing this equilibrium remain elusive. In the present study, we identify FBXO44 as a crucial regulator of Rac1 nucleocytoplasmic shuttling through its interaction with MTSS1. In gastric cancer (GC), FBXO44 orchestrates dual ubiquitination programs on MTSS1: K63-linked polyubiquitination promotes Rac1 nuclear translocation to drive cytoskeletal remodeling, whereas K11-linked modification triggers MTSS1 proteasomal degradation to restrict Rac1 nuclear trafficking. Structural analysis reveals that FBXO44 engages MTSS1 through distinct domains, dynamically balancing these opposing ubiquitination events through precise control MTSS1 protein levels, thereby calibrating actin cytoskeletal dynamics. Clinically, this regulatory axis maintains an oncogenic equilibrium-FBXO44 overexpression correlates with Rac1 signaling activation in progressive GC patients. Therapeutically, pharmacological disruption of this balance using the novel inhibitor DQ2405 achieves dual anti-tumor effects: suppressing tumor growth and metastatic capacity. Our findings establish FBXO44-mediated Rac1 spatiotemporal control as a druggable strategy for actin-cytoskeleton targeted therapy, providing both mechanistic insights into cytoskeletal homeostasis and a translational framework for GC treatment.