Mapping the Bioenergetic Landscape of Oral Cancer Stem Cells: A Systematic Review

Area of Science:

• Oncology
• Cell Biology
• Mitochondrial Biology

Background:

• Oral squamous cell carcinoma (OSSC) exhibits high lethality, often linked to drug resistance mediated by cancer stem cells (CSCs).
• Mitochondrial reprogramming is crucial for CSC survival, self-renewal, and redox control in OSSC.

Purpose of the Study:

• To systematically review mitochondrial mechanisms sustaining CSCs in OSSC.
• To evaluate the therapeutic relevance of these mitochondrial pathways in OSSC.

Main Methods:

• Systematic literature search following PRISMA guidelines.
• Data extraction on mitochondrial biogenesis, dynamics, mitophagy, and redox regulation in oral CSCs.
• Analysis of molecular pathways, functional roles, and pharmacological targeting.

Main Results:

• Mitochondrial remodeling via biogenesis (PGC-1α/ERRα), fission (DRP1), mitophagy (BNIP3/PINK1), and antioxidant signaling (NRF2) supports OSSC CSCs.
• These pathways enhance metabolic flexibility, drug tolerance, and activate stemness regulators (EGFR/JNK/SOX2, YAP/CCN1, SIRT1/PGC-1α).
• Targeting agents (DRP1 inhibitors, SIRT1/ERRα antagonists, melatonin, verteporfin) show potential to sensitize CSCs to therapy.

Conclusions:

• Mitochondria are central regulators of OSSC CSC biology and viable therapeutic targets.
• Integrating mitochondrial dynamics, metabolism, and redox control is key to overcoming OSSC resistance.
• Further research is needed to translate these findings into effective OSSC therapies.