The metallic trinity: Understanding the roles and interplay of copper, zinc, and iron in pulmonary fibrosis – A comprehensive review

Pulmonary fibrosis (PF) is a group of debilitating chronic lung diseases characterized by progressive scarring of the lung parenchyma. Despite advances in understanding its multifactorial pathogenesis, these insights have yet to translate into broadly effective treatment options. Emerging evidence underscores the critical roles of essential trace metals in driving fibrotic progression. In this review, we introduce the Metallic Trinity framework, which conceptualizes copper, zinc, and iron as an interdependent network within the pulmonary metallome. Notably, perturbations in any single metallic component disrupt the homeostasis of the others, initiating a cascade of molecular and cellular events that promote fibrogenesis. Drawing on data from both preclinical models and clinical studies, we delineate the individual roles and dynamic crosstalk among these metals in shaping the fibrotic lung microenvironment. This integrated perspective provides novel insights into the mechanisms by which trace metal imbalances contribute to aberrant tissue remodeling, inflammation, and cellular dysfunction. Furthermore, we explore therapeutic strategies aimed at restoring metal equilibrium and highlight the potential of these elements as biomarkers. By reframing PF through the lens of trace metal interdependence, the Metallic Trinity paradigm provides a rationale for exploring new strategies for precision diagnostics and targeted interventions, with the potential to improve therapeutic approaches for this devastating condition.