Abstract
INTRODUCTION: Qiwei Tiexie Pill (QWTX) is a Tibetan medicine formulation containing processed iron powder that requires systematic safety evaluation. This study aimed to assess the acute toxicological mechanisms of QWTX and its key mineral component, processed iron powder. METHODS: An integrative approach combining histopathological examination, serum biochemistry, and multi-platform metabolomics (1H NMR and LC-MS) was employed to evaluate toxicological responses in Sprague-Dawley rats following 7-day oral administration. RESULTS: While both treatments preserved hepatic structural integrity without inducing hepatotoxicity, significant renal effects were observed in a dose- and formulation-dependent manner. High-dose processed iron powder caused moderate renal histopathological alterations, primarily vascular changes and hemorrhage, alongside metabolic disruptions in both liver and kidney. QWTX, despite inducing significant metabolic perturbations at high dose, maintained normal renal architecture, indicating a protective effect conferred by its herbal components. Metabolomic and biochemical analyses revealed systemic metabolic reprogramming across four interdependent physiological domains: energy metabolism characterized by TCA cycle impairment and enhanced BCAA catabolism; oxidative stress evidenced by glutathione depletion and lipid peroxidation; nitrogen metabolism showing a "hepato-renal disconnect"; and neuroendocrine regulation with widespread hormone pathway dysregulation. DISCUSSION: QWTX demonstrated a superior safety profile compared to processed iron powder alone, particularly in preserving renal structure and mitigating iron-associated nephrotoxicity. However, high-dose QWTX still triggered significant oxidative and metabolic stress, underscoring the importance of dose optimization in clinical use. These findings provide a systems-level understanding of the acute toxicological profile of QWTX and processed iron powder, supporting the traditional principles of herbal-metal synergy in Tibetan medicine while highlighting the need for long-term safety studies to evaluate cumulative mineral exposure and chronic metabolic effects.