Cadmium‐Induced Ferroptosis: Critical Evidence Assessment, Mechanistic Paradoxes, Dose Realism, and Translational Gaps in Toxicological Research

ABSTRACT

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.