Cuproptosis in endodontics: potential mechanisms and therapeutic applications

INTRODUCTION: Cuproptosis is a recently identified copper-dependent form of regulated cell death that is distinct from apoptosis, pyroptosis, and ferroptosis. Its relevance to endodontic disease remains poorly understood despite increasing evidence that copper dyshomeostasis influences oxidative stress, mitochondrial dysfunction, and inflammatory tissue destruction. METHODS: A structured PubMed search was conducted up to April 27, 2026, using terms related to cuproptosis, copper, endodontics, pulpitis, and apical periodontitis. Original studies, reviews, and mechanistic reports relevant to the topic were included. Evidence from oncology, microbiology, and materials science was considered only when it had clear relevance to pulpal inflammation, apical periodontitis, endodontic infection, or copper-based therapeutic strategies. RESULTS: Cuproptosis occurs when excess copper binds lipoylated mitochondrial proteins and destabilizes iron-sulfur cluster proteins, causing proteotoxic stress and cell death. In pulpitis, oxidative stress, altered glutathione metabolism, and bacterial virulence factors may promote copper accumulation and cuproptosis in odontoblast lineage cells. Recent human pulpitis evidence confirms copper overload and cuproptosis activation. In periapical lesions, excess copper may intensify osteoclastogenesis and bone resorption through altered glycogen metabolism and pentose phosphate pathway activity. Copper-based materials may also induce cuproptosis-like bacterial death, suggesting potential antimicrobial value in endodontics. Therapeutic approaches include copper-regulating nanomaterials, ionophores, and microenvironment-responsive delivery systems, although toxicity, resistance, and biomarker validation remain concerns. CONCLUSIONS: Given the limited direct endodontic evidence, this conceptual framework suggests that cuproptosis may link copper dyshomeostasis with pulpal inflammation, periapical bone destruction, and bacterial killing. The biological role of cuproptosis warrants further investigation in endodontics.