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

  • Authors:
    • Angelina Daher
    • Zahraa Assi
    • Amjad Kanaan
    • Ahmad Al Khatib
    • Mirvat El Sibai
  • View Affiliations / Copyright

    Affiliations: Department of Biological Sciences, Lebanese American University, Beirut 1102 2801, Lebanon, Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, P.O. Box 100 Tripoli, Lebanon, Department of Internal Medicine and Gastroenterology, Hesse Clinic, Korbach Municipal Hospital, 34497 Korbach, Germany
    Copyright: © Daher et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 143
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    Published online on: June 3, 2026
       https://doi.org/10.3892/or.2026.9148
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Abstract

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.
View Figures

Figure 1

Metastatic cascade with energetic and
mechanical demands. This schematic illustrates the sequential steps
of metastasis from the primary tumor microenvironment to the
metastatic site, highlighting specific energy and signaling
requirements. At the invasion and intravasation steps, cancer cells
rely on local ATP production and Rho GTPase signaling to drive
actin remodeling and cytoskeletal contractility required for matrix
degradation and endothelial penetration. During circulation,
mitochondrial-derived ROS act as adaptive signals that promote cell
survival in the bloodstream. At extravasation, Rho GTPases again
support cytoskeletal reorganization, while mitochondrial metabolism
provides bioenergetic support for barrier crossing. Finally, at
colonization in the distant site, cells depend on ATP production
and FAO to adapt to nutrient limitations and establish
proliferative growth. Overall, this process reflects a
bidirectional metabolic-mechanical feedback loop, in which
mitochondrial metabolism and Rho GTPase-driven cytoskeletal
dynamics reciprocally reinforce metastatic progression. ROS,
reactive oxygen species; FAO, fatty acid oxidation.

Figure 2

Mitochondrial coordination of
metastatic energy metabolism and motility. Metastatic cancer cells
rewire core mitochondrial pathways (OXPHOS, TCA, FAO) to produce
ATP, biosynthetic precursors, and redox signals that support
motility. ROS and HIF-1α activate Rho/FAK signaling, driving
cytoskeletal remodeling. Mitochondrial dynamics (DRP1-mediated
fission and MFN1/2-mediated fusion) distribute ATP and maintain
networked metabolism to meet energetic and biosynthetic demands.
Key upstream regulators (PGC-1α, MYC, AMPK/mTOR, NRF2) orchestrate
metabolic rewiring, dynamics, and redox balance. The integrated
output enhances energy availability, biomass synthesis, ROS
signaling, and promotes cancer cell migration, invasion, and
colonization. OXPHOS, oxidative phosphorylation; TCA, tricarboxylic
acid; FAO, fatty acid oxidation; ROS, reactive oxygen species.

Figure 3

Regulation and downstream signaling
of Rho GTPases in cancer metastasis. Extracellular stimuli,
including growth factors, integrin-ECM interaction, and chemokines,
activate Rho GTPases (RhoA, Rac1, Cdc42). These proteins function
as molecular switches, cycling between inactive GDP-bound and
active GTP-bound states. Their activity is tightly regulated by
GEFs, GAPs and GDIs, where GEF hyperactivation or GAP loss leads to
sustained Rho GTPase signaling. Activated RhoA drives ROCK-mediated
stress fiber assembly and actomyosin contractility, facilitating
amoeboid motility; Rac1 promotes lamellipodia formation via
WAVE/Arp2/3 and generates localized ROS through NOX complexes,
amplifying pro-migratory signals and mesenchymal motility; Cdc42
orchestrates filopodia formation, establishes polarity, and
regulates MMP trafficking for ECM remodeling. Collectively, this
coordinated signaling network drives cytoskeletal remodeling,
directional migration, ECM degradation, and ultimately facilitates
cancer cell invasion and metastatic dissemination. ECM,
extracellular matrix; GEF, guanine nucleotide exchange factor; GAP,
GTPase-activating protein; GDI, guanine nucleotide dissociation
inhibitor; ROS, reactive oxygen species; MMP, matrix
metalloproteinase; NOX, NADPH oxidase.

Figure 4

Molecular nodes integrating
mitochondrial function with Rho GTPase-mediated cytoskeletal
regulation in cancer metastasis. Metastatic signaling converges on
three key molecular nodes linking mitochondrial function to Rho
GTPase-mediated cytoskeletal remodeling. Energy-sensing kinases
AMPK and mTORC1 translate nutrient and energy availability into
distinct cytoskeletal outputs: AMPK inhibits RhoA-ROCK signaling
via phosphorylation-dependent mechanisms, reducing actomyosin
contractility, whereas mTORC1 promotes Rac1-driven protrusion
through activation of the WAVE-Arp2/3 complex, leading to
lamellipodia formation (68,75).
Mitochondrial ROS, particularly H2O2, act as redox signaling
molecules by oxidizing cysteine residues in regulatory proteins,
leading to activation of Src (p-Tyr416) and downstream Rho-GEFs,
thereby promoting Rac1 and RhoA signaling (17,99,100,102,119). In parallel, mitochondrial
dynamics, are regulated by DRP1 phosphorylation (Ser616 promotes
fission; Ser637 inhibits fission) and Miro1/2-mediated trafficking,
which enables redistribution of mitochondria and localized ATP
supply to support Rac1- and Cdc42-driven actin polymerization
(67). These pathways form a
bidirectional feedback loop in which mitochondrial metabolism (ATP
and ROS) drives Rho GTPase activation, while Rho-dependent
cytoskeletal remodeling regulates mitochondrial positioning.
Together, these nodes converge to drive cytoskeletal remodeling,
contractility, extracellular matrix degradation, and directional
migration, enhancing invasive and metastatic potential.
Therapeutically, this network highlights actionable targets,
including AMPK activators (+), mTORC1 inhibitors (−), DRP1 or
mitochondrial trafficking inhibitors (−), and context-dependent ROS
modulators (±). ROS, reactive oxygen species; p-, phosphorylated;
DRP1, dynamin-related protein 1.

Figure 5

Mechanistically complementary dual
targeting of mitochondria and Rho GTPases to inhibit cancer
metastasis. Mitochondria-targeting agents, such as tigecycline or
doxycycline, inhibit OXPHOS, leading to depletion of ATP and
reduction of mitochondrial ROS. This limits the energy supply
necessary for actin polymerization and dampens pro-migratory
signaling via Src kinase and Rho GTPases. Simultaneously,
siRNA-mediated silencing of Rho GTPases (RhoA, Rac1 and Cdc42)
directly dismantles the cytoskeletal machinery required for
migration and invasion. Individually, cells may compensate, by
upregulating glycolysis or switching migration modes, but combined
targeting creates a synergistic effect, blocking both the “fuel”
and the “engine” of metastasis. Preclinical studies demonstrate
that this dual approach is expected to reduce invasive capacity
more effectively than monotherapies. OXPHOS, oxidative
phosphorylation; ROS, reactive oxygen species; siRNAs, small
interfering RNAs.
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Copy and paste a formatted citation
Spandidos Publications style
Daher A, Assi Z, Kanaan A, Al Khatib A and El Sibai M: Dual targeting of mitochondrial metabolism and Rho GTPase signaling to suppress cancer metastasis (Review). Oncol Rep 56: 143, 2026.
APA
Daher, A., Assi, Z., Kanaan, A., Al Khatib, A., & El Sibai, M. (2026). Dual targeting of mitochondrial metabolism and Rho GTPase signaling to suppress cancer metastasis (Review). Oncology Reports, 56, 143. https://doi.org/10.3892/or.2026.9148
MLA
Daher, A., Assi, Z., Kanaan, A., Al Khatib, A., El Sibai, M."Dual targeting of mitochondrial metabolism and Rho GTPase signaling to suppress cancer metastasis (Review)". Oncology Reports 56.2 (2026): 143.
Chicago
Daher, A., Assi, Z., Kanaan, A., Al Khatib, A., El Sibai, M."Dual targeting of mitochondrial metabolism and Rho GTPase signaling to suppress cancer metastasis (Review)". Oncology Reports 56, no. 2 (2026): 143. https://doi.org/10.3892/or.2026.9148
Copy and paste a formatted citation
x
Spandidos Publications style
Daher A, Assi Z, Kanaan A, Al Khatib A and El Sibai M: Dual targeting of mitochondrial metabolism and Rho GTPase signaling to suppress cancer metastasis (Review). Oncol Rep 56: 143, 2026.
APA
Daher, A., Assi, Z., Kanaan, A., Al Khatib, A., & El Sibai, M. (2026). Dual targeting of mitochondrial metabolism and Rho GTPase signaling to suppress cancer metastasis (Review). Oncology Reports, 56, 143. https://doi.org/10.3892/or.2026.9148
MLA
Daher, A., Assi, Z., Kanaan, A., Al Khatib, A., El Sibai, M."Dual targeting of mitochondrial metabolism and Rho GTPase signaling to suppress cancer metastasis (Review)". Oncology Reports 56.2 (2026): 143.
Chicago
Daher, A., Assi, Z., Kanaan, A., Al Khatib, A., El Sibai, M."Dual targeting of mitochondrial metabolism and Rho GTPase signaling to suppress cancer metastasis (Review)". Oncology Reports 56, no. 2 (2026): 143. https://doi.org/10.3892/or.2026.9148
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