Mitochondrial dysfunction-ferroptosis crosstalk drives renal fibrosis in chronic kidney disease.

Abstract

Renal fibrosis is a major pathological process in the progression of chronic kidney disease (CKD). It contributes to progressive loss of kidney function and may ultimately lead to end-stage renal disease. Mitochondrial homeostasis plays a central role in cellular energy metabolism and oxidative balance, while mitochondrial dysfunction is closely associated with various kidney diseases. Ferroptosis, an iron-dependent form of regulated cell death, has been increasingly implicated in kidney injury and fibrotic remodeling. This review summarizes molecular mechanisms linking mitochondrial homeostasis and ferroptosis in renal fibrosis. We discuss how disrupted iron metabolism can induce mitochondrial dysfunction and sensitize renal cells to ferroptosis, thereby promoting fibrogenesis. We integrate recent evidence on the interplay among iron homeostasis, mitochondrial dysfunction, oxidative stress, and regulated cell death pathways in renal fibrosis. We also highlight candidate therapeutic targets, including iron chelation and iron-export regulation (e.g., the FPN-hepcidin axis), restoration of the GPX4-System Xc- antioxidant defense, activation of Nrf2 signaling, and modulation of mitochondrial quality control/mitophagy.

Key Findings

• Mitochondrial dysfunction and ferroptosis are interconnected processes that drive renal fibrosis in chronic kidney disease.
• Disrupted iron metabolism induces mitochondrial dysfunction and sensitizes renal cells to ferroptosis, promoting fibrogenesis.
• Therapeutic targets include iron chelation, regulation of the FPN-hepcidin axis, restoration of GPX4-System Xc- antioxidant defense, activation of Nrf2 signaling, and modulation of mitochondrial quality control/mitophagy.

Clinical Significance

Citation

Zeng Lianlin, Zhu Lutao, Xu Hailanet al.. Mitochondrial dysfunction-ferroptosis crosstalk drives renal fibrosis in chronic kidney disease. Renal failure. 2026-Dec.