Dual targeting of mitochondrial metabolism and Rho GTPase signaling to suppress cancer metastasis (Review)

Despite the numerous advances in cancer therapy, disseminated neoplastic disease remains largely incurable and the primary cause of cancer-related deaths. This process demands substantial bioenergetic and mechanical adaptability, orchestrated by two core cellular systems: Mitochondrial metabolism and Rho GTPase-driven cytoskeletal dynamics. Traditionally studied independently, these systems form a tightly integrated, bidirectional network. Mitochondria supply ATP and reactive oxygen species (ROS) that fuel and signal through Rho GTPases to drive invasion, while cytoskeletal remodeling and cell polarity direct mitochondrial positioning to meet local energy demands. The present review synthesizes the molecular mechanisms underlying this metabolic-mechanical crosstalk and highlights a feedforward loop in which mitochondrial oxidative phosphorylation-derived ATP and ROS activate Rho GTPase signaling, while Rho-driven cytoskeletal remodeling increases energy demand and promotes mitochondrial redistribution, thereby reinforcing metastatic progression. Critically, this interdependence represents a therapeutic vulnerability. A dual-targeting strategy was discussed, combining Rho GTPase silencing (via small interfering RNA) with mitochondrial inhibition (via repurposed antibiotics) to simultaneously disrupt the cytoskeletal ‘engine’ and its metabolic ‘fuel’. Such approaches may overcome compensatory adaptive resistance that limits single-target therapies. By framing mitochondrial and Rho GTPase signaling as an integrated functional axis, the present review provides a mechanistic and translational framework for the development of next-generation, combination-based anti-metastatic therapies.