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

Objectives Oral squamous cell carcinoma (OSSC) remains highly lethal, with resistance largely driven by cancer stem cells (CSCs). Mitochondrial reprogramming supports CSC redox control, self‐renewal, and survival. This systematic review aimed to synthesize mitochondrial mechanisms sustaining CSCs in OSCC and evaluate their therapeutic relevance. Methods Following PRISMA guidelines and a PROSPERO protocol (CRD420251088208), we searched major databases for studies investigating mitochondrial biogenesis, dynamics, mitophagy, or redox regulation in oral CSCs. Extracted data included molecular pathways, functional roles, and pharmacological targeting. Results Ten studies were eligible. Evidence shows that mitochondrial remodeling, through PGC‐1α/ERRα‐mediated biogenesis, DRP1‐dependent fission, BNIP3/PINK1‐regulated mitophagy, and NRF2‐driven antioxidant signaling, supports metabolic flexibility and drug tolerance. These pathways activate stemness regulators, including EGFR/JNK/SOX2, YAP/CCN1, and SIRT1/PGC‐1α, promoting adaptation and recurrence. Pharmacological interventions targeting these nodes, such as DRP1 inhibitors, SIRT1 or ERRα antagonists, and mitophagy‐modulating agents (melatonin, verteporfin), showed potential to sensitize CSCs to conventional therapies. Conclusion Mitochondria act as central regulators of CSC biology in OSCC and represent actionable therapeutic targets. Integrating mitochondrial dynamics, metabolism, and redox control provides a framework for overcoming resistance. Further preclinical and clinical studies are needed to translate these vulnerabilities into effective OSCC therapies. Trial Registration PROSPERO, CRD420251088208