Cadmium-Induced Ferroptosis: Critical Evidence Assessment, Mechanistic Paradoxes, Dose Realism, and Translational...

Cadmium (Cd) is a globally persistent toxic metal with extraordinary biological retention and cumulative tissue toxicity. Ferroptosis has emerged as a proposed mechanism of Cd-induced cytotoxicity. However, current research is characterized by profound methodological heterogeneity, supraphysiological dosing, incomplete ferroptosis validation, overlapping cell death pathways, and inconsistent mechanistic interpretations. Here, we perform a systematic, mechanism-centered, and dose-aware critical review of Cd-induced ferroptosis, based on a newly established four-tier causality framework that distinguishes genuine ferroptosis from non-specific oxidative injury. We integrate existing data into three mechanistic axes: LIP expansion via ferritinophagy, dysregulation of the Nrf2/SLC7A11/GPX4 antioxidant defense system, and mtROS amplification. At the same time, we highlight two major mechanistic paradoxes: the HO-1 functional switch and the dose-duration discrepancy. Based on a critical review of all available data, current data do not support ferroptosis as a universal mechanism of Cd toxicity. Instead, it is a context- and dose-dependent phenomenon that appears to become most prominent under acute high-dose exposure conditions. Finally, we propose a comprehensive research roadmap including physiologically realistic exposure models, establishment of ferroptosis-specific validation standards, ferroptosis biomarker development, and mechanistic resolution of the HO-1 and dose-duration paradoxes. This work aims to refine conceptual oversimplifications, address methodological weaknesses, and establish a rigorous toxicological foundation for future research.